JP2021107465A - N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide hydrochloride salts - Google Patents

Abstract

To provide stable novel salt forms of N-(cyanomethyl)-4-(2-(4- morpholinophenylamino)pyrimidin-4-yl)benzamide and their therapeutic use, which are suitable for the preparation of pharmaceutical formulations.SOLUTION: The present invention relates to stable novel salt forms of N-(cyanomethyl)-4-(2-(4- morpholinophenylamino)pyrimidin-4-yl)benzamide, and their therapeutic use, which are suitable for the preparation of pharmaceutical formulations thereof.SELECTED DRAWING: Figure 1

Description

Field This application applies to stable novel salt forms of N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamides suitable for the preparation of their pharmaceutical formulations, and these. Regarding the therapeutic use of.

Background Inhibition of Janus kinase (JAK) has been evaluated in the treatment of hyperproliferative disorders. Several JAK inhibitors have been developed: ruxolitinib, tofacitinib, baricitinib, restortinib, pacritinib, fedratinib, XL019, SB15
18 and AZD1480 have been developed (Sonbol, Ther. Adv. Hematol., Volume 4:
15-35 pages, 2013). Compound N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) is JAK
It is a kinase inhibitor.

In clinical studies, CYT-0387 is a hyperproliferative disorder such as polycythemia vera (
It is effective in treating PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Patients with myelofibrosis who received CYT-0387 also exhibited improvement in anemia and / or splenic response (each incorporated herein by reference in its entirety, U.S. Pat. No. 8,486,941. Issue and US Patent Application Publication No. 201
See No. 4-0073643).

It is desired to have various forms of compounds suitable for the preparation of pharmaceutical formulations containing CYT-0387 and their therapeutic use.

U.S. Pat. No. 8,486,941 U.S. Patent Application Publication No. 20140073643

Sonbol, Ther. Adv. Hematol., Volume 4, pp. 15-35, 2013

を対象とし、これは、約１３．５°、２０．９°、２６．１°、２６．６°、および２８
．３°２−θ±０．２°２−θにピークを有する粉末Ｘ線回折（ＸＲＰＤ）パターンを有
する。 Brief Abstract The present invention is directed to a novel CYT-0387 form.
In one aspect, the present invention is CYT-0387 monohydrochloride anhydrous form I:

Of which are about 13.5 °, 20.9 °, 26.1 °, 26.6 °, and 28.
.. It has a powder X-ray diffraction (XRPD) pattern with a peak at 3 ° 2-θ ± 0.2 ° 2-θ.

を対象とし、これは、約７．７°、１９．３°、２４．０°、２５．７°、および２９．
６°２−θ±０．２°２−θにピークを有する粉末Ｘ線回折（ＸＲＰＤ）パターンを有す
る。 In another aspect, the present invention relates to CYT-0387 dihydrochloride monohydrate form II:

Of which are about 7.7 °, 19.3 °, 24.0 °, 25.7 °, and 29.
It has a powder X-ray diffraction (XRPD) pattern with a peak at 6 ° 2-θ ± 0.2 ° 2-θ.

を対象とし、これは、約１２．７°、１４．６°、１７．８°、１９．７°、および２３
．３°２−θ±０．２°２−θにピークを有する粉末Ｘ線回折（ＸＲＰＤ）パターンを有
する。 In another aspect, the present invention relates to CYT-0387 monohydrochloride anhydrous Form III (Form III):

Of which are approximately 12.7 °, 14.6 °, 17.8 °, 19.7 °, and 23.
.. It has a powder X-ray diffraction (XRPD) pattern with a peak at 3 ° 2-θ ± 0.2 ° 2-θ.

The present invention also provides a composition comprising a pharmaceutical composition, a kit comprising a compound, and a method of using and preparing the pharmaceutical composition. The pharmaceutical compositions provided herein are JAK.
It is useful for treating diseases, disorders, or conditions mediated by. In certain embodiments, the JAK-mediated disease, disorder, or condition is myeloproliferative and cancerous.

In one embodiment, the application is in a dosage form comprising CYT-0387 Form III, particularly in the dosage form as a tablet, more specifically in an amount corresponding to the CYT-0387 free base between 30 and 250 mg. 0387 Dosage forms containing Form III are targeted. In one embodiment, the dosage form is 1
CYT-0387 Form II in an amount corresponding to 00-200 mg of CYT-0387 free base
including.

In a further embodiment, the application provides a pharmacokinetic profile that is substantially similar to a dosage form or pharmaceutical composition comprising CYT-0387 anhydrous form I in an amount equivalent to 300 mg of CYT-0387 free base. , A dosage form or pharmaceutical composition comprising CYT-0387 Form III in an amount corresponding to 200 mg of CYT-0387 free base.

In some embodiments, the present application is directed to a dosage form comprising CYT-0387 dihydrochloride monohydrate Form II as a tablet, which dosage form is between about 100 mg and about 300 mg of CYT-.
CYT-0387 Dihydrochloride monohydrate form II is contained in an amount corresponding to 0387 free base. In certain embodiments, the present application is directed to a dosage form comprising CYT-0387 dihydrochloride monohydrate Form II as a tablet, which dosage form is about 100 mg, about 150 mg, about 200 mg.
CYT in an amount corresponding to about 250 mg, or about 300 mg of CYT-0387 free base.
-0387 Dihydrochloride monohydrate contains Form II. In certain embodiments, the present application is directed to a dosage form comprising CYT-0387 dihydrochloride monohydrate form II as a tablet, which dosage form corresponds to approximately 100 mg of CYT-0387 free base. CYT-0387 Dihydrochloride Monohydrate Form II is included in the amount to be added. In certain embodiments, the present application, as a tablet, is CYT-.
Targeting dosage forms containing 0387 dihydrochloride monohydrate form II, this dosage form comprises CYT-0387 dihydrochloride monohydrate form II in an amount corresponding to approximately 200 mg of CYT-0387 free base. .. In certain embodiments, the present application is directed to a dosage form comprising CYT-0387 dihydrochloride monohydrate Form II as a tablet, which dosage form corresponds to approximately 250 mg of CYT-0387 free base. Includes CYT-0387 Dihydrochloride Monohydrate Form II in quantity. In certain embodiments, the present application is directed to a dosage form containing CYT-0387 dihydrochloride monohydrate Form II as a tablet, which equivalent to approximately 300 mg of CYT-0387 free base. CYT-0387 Dihydrochloride Monohydrate Form II is included in the amount to be added. In an additional embodiment, the application is 3
200 mg of CYT-0387 provides a pharmacokinetic profile substantially similar to a dosage form or pharmaceutical composition comprising CYT-0387 dihydrochloride monohydrate Form II in an amount equivalent to 00 mg of CYT-0387 free base. Dosage forms or pharmaceutical compositions comprising CYT-0387 dihydrochloride monohydrate Form II in an amount corresponding to the free base are targeted.

Kits also include compounds of formula (I) or pharmaceutically acceptable salts, isomers, or mixtures thereof. The kit may further include labels and / or instructions for using the compound in the treatment of a disease, disorder, or condition in humans in need thereof.

Products also include a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or mixture thereof, and a container. In one embodiment, the container is a vial, bottle, ampoule,
It can be a pre-filled syringe or an IV bag.

XRPD of N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) anhydrous form I. DSC of N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) anhydrous form I. N- (Cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) dihydrochloride anhydrous form I TGA. N- (Cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) DVS of anhydrous form I. N- (Cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate XRPD pattern for Form II. XRPD pattern for N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride anhydrous form I. XRPD pattern for N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride anhydrous form III. DSC for N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate Form II. DSC for N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride anhydrous form I. DSC for N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride anhydrous form III. N- (Cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate TGA for Form II. N- (Cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride TGA for anhydrous form I. N- (Cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride TGA for anhydrous form III. N- (Cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate DVS for Form II.

Detailed Description The following description describes exemplary compositions and methods, parameters and the like. However, it should be recognized that such description is not intended to be limited to the scope of the present disclosure and is instead provided as a description of an exemplary embodiment.

JAK inhibitor C disclosed in US Pat. No. 8,486,941 having the following structure:
YT-0387, ie N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide:

The anhydrous form of CYT-0387 dihydrochloride is disclosed in PCT application WO2012 / 071612. CYT-0387 dihydrochloride anhydride has the following structure:

CYT-0387 Anhydrous dihydrochloride form I (form IV) XRPD, differential scanning calorimetry (D)
SC), thermogravimetric analysis (TGA), and dynamic vapor adsorption (DVS) are shown in FIGS. 1, 2, 3, and 4, respectively.

The present application is for another novel form of CYT-387, ie monohydrochloride anhydrous form I (form I).
, Dihydrochloride monohydrate form II (form II), and monohydrochloride anhydrous form III (form III)
)I will provide a.

As used herein, the terms "form I" or "CYT-0387 form I" are used to refer to CYT-0387 monohydrochloride anhydrous form I, "form II" or "form II" or "form I".
The term "CYT-0387 Form II" refers to CYT-0387 dihydrochloride hydrate, CYT-
0387 dihydrochloride monohydrate, or CYT-0387 dihydrochloride monohydrate Form II, used to refer to the term "form III" or "CYT-0387 form III".
Used to refer to YT-0387 Anhydrous Monohydrochloride Form III, "Form IV" or "C"
The term "YT-0387 Form IV" is used to refer to CYT-0387 Anhydrous Dihydrochloride Form I.

In one embodiment, Form I or CYT-0387 Form I is the XRP shown in FIG.
Characterized by D, DSC in FIG. 9, or TGA in FIG. In one embodiment, Form I or CYT-0387 Form I is about 13.5 °, 20.9 °, 26.1 °, 26.
It has an XRPD pattern with peaks at 6 ° and 28.3 ° 2-θ ± 0.2 ° 2-θ.

In some embodiments, Form II or CYT-0387 Form II is characterized by the XRPD shown in FIG. 5, the DSC in FIG. 8, the TGA in FIG. 11, or the DVS in FIG. In one embodiment, Form II or CYT-0387 Form II is about 7.7 °, 19
.. It has an XRPD pattern with peaks at 3 °, 24.0 °, 25.7 °, and 29.6 ° 2-θ ± 0.2 ° 2-θ.

In other embodiments, Form III or CYT-0387 Form III is characterized by the XRPD shown in FIG. 7, the DSC in FIG. 10, or the TGA in FIG. In one embodiment, Form III or CYT-0387 Form III is about 12.7 °, 14.6 °.
, 17.8 °, 19.7 °, and XRPD patterns with peaks at 23.3 ° 2-θ ± 0.2 ° 2-θ.

In certain embodiments, Form IV or CYT-0387 Form IV is characterized by the XRPD shown in FIG. 1, the DSC in FIG. 2, or the TGA in FIG. In one embodiment, Form IV or CYT-0387 Form IV is about 5.5 °, 10.1 °, 14.
XRPD with peaks at 9 °, 25.1 °, and 26.6 ° 2-θ ± 0.2 ° 2-θ
Has a pattern.

From the results of this application, it was found that CYT-0387 dihydrochloride monohydrate (form II) has higher stability than other salts or forms of CYT-387 under certain conditions. From the results described herein, CYT-387 form II is such CYT-.
It has also been found that the properties of Form II make it more appropriate to develop or incorporate various synthesis or methods. In one embodiment, CYT-387 Form II is suitable for use in pharmaceutical compositions in tablet format. In addition, the experiments described herein have shown formulations of tablets that exhibit bioavailability properties similar to those of capsule formulations. In certain embodiments, 200 mg of free base CY
Tablets containing CYT-0387 dihydrochloride monohydrate form II in an amount corresponding to T-0387
It provides bioavailability similar to capsules containing CYT-0387 Anhydrous Form I of CYT-0387 in an amount corresponding to CYT-0387 of 300 mg of free base.

The results of this application show that CYT-0387 Anhydrous Dihydrochloride Form I is hygroscopic and physically unstable when exposed to moisture. In addition, the results described below show that CYT-0387 dihydrochloride monohydrate form II is a thermodynamically stable form of dihydrochloride under conditions suitable for production and / or storage. ing. In addition, in this application, the use of propyl gallate (free radical scavenger oxidant) is C in aqueous solution and tablet formulation.
It is described that it is effective in inhibiting or preventing the oxidative decomposition of YT-0387 dihydrochloride monohydrate form II. In addition, the results show CYT-0387 dihydrochloride monohydrate form II.
Suggests that it exhibits higher bioavailability compared to CYT-0387 anhydrous form I and CYT-0387 free base.

In a further embodiment, the invention also provides amorphous N- (cyanomethyl) -4- (2).
-(4-Morpholine phenylamino) pyrimidin-4-yl) benzamide (CYT-0)
387) Provide dihydrochloride monohydrate. In additional embodiments, the present invention is also amorphous N.
-(Cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) monohydrochloride anhydride and amorphous N- (cyanomethyl) -4- (2-) (4-Molholinophenylamino) pyrimidine-4-yl) benzamide (CYT-0387) monohydrochloride anhydride is provided. In another embodiment, the invention also
Amorphous N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) dihydrochloride and amorphous N- (cyanomethyl) -4- (2- (4-Molholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) monohydrochloride is provided.

In certain embodiments, N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) dihydrochloride monohydrate form II is in crystalline form. ..

In a further embodiment, N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) monohydrochloride anhydrous form I
Is in crystalline form.

In certain embodiments, N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) monohydrochloride anhydrous form III is in crystalline form.

In one embodiment, the crystal morphology is characterized by interstitial plane spacing as determined by the powder X-ray diffraction pattern (XRPD). The diffraction pattern of the XRPD is usually represented by plotting the peak intensity vs. the peak position, that is, the diffraction angle 2θ (2 theta) (degrees). Strength is often given to parentheses using the following abbreviations: very strong = vst; strong = st; intermediate = m; weak = w; and very weak = vw. By selecting the characteristic peaks of a given XRPD according to their peak positions and their relative intensities, this crystal structure can be conveniently distinguished from others.

Those skilled in the art will recognize that measurements of XRPD peak position and / or intensity for a given crystalline form of the same compound will vary within tolerance. The value of degree 2θ allows an appropriate margin of error. The margin of error is usually represented by "±". For example, a degree 2θ of about "8.7 ± 0.3" is about 8.7 + 0.3, or about 9.0 to about 8.7-0.3, or about 8.
.. Represents a range up to 4. Depending on the sample preparation technique, the calibration technique applied to the device, the variation of human operation, etc., a person skilled in the art would have an appropriate tolerance for XRPD of ± 0.5; ±.
We recognize that it can be 0.4; ± 0.3; ± 0.2; ± 0.1; ± 0.05; or less. In certain embodiments of the invention, the XRPD tolerance is ± 0.2.

Additional details of the methods and instruments used for XRPD analysis are described in the Examples section.

CYT-0387 Anhydrous Dihydrochloride Form I, CYT-0387, Dihydrochloride Monohydrate Form II
, CYT-0387 Monochloride Anhydrous Form I and CYT-0387 Monochloride Anhydrous Form III
The XRPD peaks for are found in Table 1 below.

As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless otherwise indicated by the context in which they are used.

References to a value or parameter labeled "about" herein include (and describe) embodiments that cover the value or parameter itself. For example, a description referring to "about X" includes a description of "X". In certain embodiments, the term "about" is the indicated amount ± 10%.
including. In other embodiments, the term "about" comprises the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Also, the singular forms "one (a)" and "the (the)" include references to plurals unless explicitly indicated in the context. Thus, for example, a reference to "the compound" includes a plurality of such compounds, and a reference to "the assay" refers to one or more assays and their equivalents known to those of skill in the art. include.

"Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms and useful compounds for the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use. Refers to other materials.

A "pharmaceutically acceptable salt" or "physiologically acceptable salt" is one that retains the biological efficacy and properties of the underlying compound and is not biologically or otherwise harmful. , Refers to salts of pharmaceutical compounds. There are acid addition salts and base addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Acids and bases useful for reaction with the underlying compounds for forming pharmaceutically acceptable salts (acid or base salts, respectively) are known to those skilled in the art. Similarly, methods of preparing pharmaceutically acceptable salts from the underlying compounds (by disclosure) are known to those of skill in the art, eg, Berger et al., Journal of Phar.
It is disclosed in maceutical Science, January 1977, Vol. 66, No. 1, and other sources. When the compounds described herein are obtained as acid addition salts, their free base can be obtained by basicizing a solution of this acid salt. Conversely, if the product is a free base, the addition salt, especially the pharmaceutically acceptable addition salt, will use this free base as a suitable organic solvent according to conventional procedures for preparing acid addition salts from base compounds. It can be produced by dissolving in and treating the solution with an acid. "Treatment" or "treat" is a technique for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical outcomes can include one or more of the following: a) Inhibition of a disease or condition (eg, reduction of one or more symptoms resulting from the disease or condition, and / or disease or Reduction of degree of condition); b) Slow or suppress the onset of one or more clinical symptoms associated with the disease or condition (eg, stabilize the disease or condition, prevent or delay the exacerbation or progression of the disease or condition, And / or prevention or delay of the spread of the disease or condition (eg, metastasis); and / or c) mitigation of the disease, i.e. causing regression of clinical symptoms (eg, relief of the condition, partial disease or condition) Or provide complete remission, promote the effect of another drug, delay the progression of the disease, improve quality of life, and / or prolong life).

1 to n hydrogen atoms attached to carbon atoms (n is the number of hydrogen atoms in the molecule)
, Compounds that can be replaced with a deuterium atom or D are described herein. It is known that the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds can increase resistance to metabolism and therefore, when administered to a mammal, the compounds described herein or their pharmaceutically acceptable salts, isomers, prodrugs, or It can be useful for increasing the half-life of solvates. For example, Foster, "Deuterium Isotope Effect
s in Studies of Drug Metabolism ”, Trends Pharmacol. Sci., Volume 5 (No. 12)
: See pages 524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium. In some embodiments, the compounds described herein are C.
YT-0387 Dihydrochloride Monohydrate Form II, CYT-0387 Monohydrochloride Anhydrous Form I, CY
T-0387 Anhydrous Monohydrochloride Form III, CYT-0387 Anhydrous Dihydrochloride Form IV, Compound 3, Compound 4, Compound 8, Compound 10, Compound 12, and Compound 13.

"Preventing" or "preventing" means any treatment of a disease or condition that does not cause the clinical manifestations of the disease or condition. In some embodiments, the compound can be administered to a subject (including humans) who is at risk for a disease or condition or has a family history.

The term "subject" or "patient" refers to an animal, such as a mammal (including a human), that has been or will be intended for treatment, observation, or experimentation. The methods described herein may be useful for human treatment and / or veterinary application. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. "Human in need of it" refers to a person who may or is suspected of having a disease or condition for which a particular treatment is effective, eg, being treated with a compound according to the present application. The term "subject in need of it" or "patient in need of it" may have, or is diagnosed with, a disease, disorder, or condition for which the treatment described herein is effective. Refers to a subject or patient who is or is suspected of having. In certain embodiments, (i) have not received any treatment (ie, untreated), (ii) have received previous treatment, but did not respond or showed improvement, or (iii). A subject or patient who is relapsed or resistant (ie refractory) to previous treatment. For example, the patient may have received platinum-based chemotherapy or treatment containing gemcitabine. Additional examples include patients who may relapse or be refractory to platinum-based chemotherapy or treatments containing gemcitabine.

The term "therapeutically effective amount" of a compound of the present application or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof is administered to a subject for treatment to relieve symptoms or disease. Means an amount sufficient to provide therapeutic benefits such as slowing the progression of the disease. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, but can be readily determined by one of ordinary skill in the art. In one embodiment, the therapeutically effective amount of the compounds described herein is 100 mg.
It is 150 mg, 200 mg, 250 mg, or 300 mg.

The term "inhibition" refers to a decrease in biological activity or baseline activity of a process.

Pharmaceutical Compositions and Administrations The compounds provided herein are usually administered in the form of pharmaceutical compositions. Accordingly, herein, one or more of a compound of any of the formulas disclosed herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof, as well as a carrier. Pharmaceutical compositions containing one or more pharmaceutically acceptable vehicles selected from adjuvants and excipients are also provided. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers and adjuvants. .. Such compositions are prepared by methods well known in the pharmaceutical art. For example, Remington's Pharmaceutical Scie
nces, Mace Publishing Co., Philadelphia, Pa., 17th Edition (1985); and Moder
n See Pharmaceutics, Marcel Dekker, Inc. 3rd Edition (GS Banker & CT Rhodes). As used herein, a "solvate" is formed by the interaction of a solvent with a compound. Solvates of salts of any of the compounds of the formulas described herein are also provided. Hydrate of any compound of these formulas is also provided. In addition, "prodrug" is defined in the pharmaceutical field as a bioactive derivative of a drug that is converted into a bioactive parent drug by administration to the human body by some chemical or enzymatic route.

The pharmaceutical composition can be administered in either single or multiple doses. The pharmaceutical composition can be administered by a variety of methods, including, for example, the rectal, buccal, intranasal and percutaneous routes. In certain embodiments, the pharmaceutical composition is an intraarterial injection, intravenous, intraperitoneal,
It can be administered parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
In some embodiments, the pharmaceutical composition is administered orally.

One mode of administration is done parenterally, for example by injection. As forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection, for example, sesame oil, corn oil, cottonseed oil, or peanut oil, and elixir, mannitol, glucose, etc.
Or aqueous or oily suspensions with sterile aqueous solutions and similar pharmaceutical vehicles,
Alternatively, an emulsion may be mentioned.

Oral administration may be another route for administering the compounds described herein. Administration
For example, it can be done with capsules or enteric coated tablets. When making a pharmaceutical composition comprising at least one compound of any of the formulas described herein or a pharmaceutically acceptable salt, prodrug or solvate thereof, the active ingredient is usually an excipient. Diluted with and / or encapsulated in a carrier such that it may be in the form of capsules, sachets, paper or other containers. When the excipient acts as a diluent, the excipient can be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier or vehicle for the active ingredient.
Thus, the compositions are tablets, pills, powders, lozenges, sachets, cashiers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), For example, it can be in the form of ointments, soft and hard gelatin capsules, injectable sterile solutions, and packaged sterile powders containing up to 10% by weight of the active compound.

To prepare a solid composition such as tablets, the main active ingredient is mixed with a medicinal excipient and the compound of any of the above formulas or a pharmaceutically acceptable salt, prodrug or solvent thereof. A solid preform composition containing a homogeneous mixture of Japanese products can be formed. When these pre-formal compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed in the composition, thus the composition is an equally effective unit agent such as tablets, pills and capsules. It can be easily divided into shapes.

Tablets or pills of the compounds described herein can be coated to provide a dosage form that imparts long-acting benefits, or to protect against acidic conditions in the stomach, or otherwise. Can be blended. For example, a tablet or pill can contain an internal dosing component and an external dosing component, the external dosing component being present in the form of a coat over the internal dosing component. These two components can be separated by an enteric layer that withstands disintegration in the stomach and acts to allow internal components to pass intact into the duodenum or to delay release. A variety of materials can be used for such enteric layers or coatings, such as polymer acids and materials such as shellac, cetyl alcohol, and cellulose acetate. Contains the mixture.

Specific dose levels of the compounds of the formulas described herein for any particular subject are the activity, age, weight, overall health, gender, diet, dosing time of the specific compounds used. ,
It depends on a variety of factors, including the route of administration and rate of excretion, the combination of drugs, and the severity of the particular disease of the subject being treated. For example, the dose can be expressed as the number of milligrams (mg / kg) of the compound of the formula per kilogram of body weight of the subject. About 0.01 ~
A dose of 200 mg / kg may be suitable. In some embodiments, from about 0.01
150 mg / kg may be suitable. In other embodiments, 0.05-100 mg /
A dose of kg may be suitable. Adjust doses between subjects of wide disparity, such as when using the drug in both children and adults, or when converting an effective dose in a non-human subject such as a dog to a dose suitable for a human subject. If so, it is particularly useful to normalize according to the body weight of the subject.

The compounds of this application or compositions thereof are prepared using any of the appropriate forms described above, 1 day.
It can be administered once, twice, three times, or four times. Also, administration or treatment with a compound according to any of the formulas described herein can be continued for several days, eg, in general, for example.
Treatment can be continued for at least 7, 14, or 28 days with one cycle of treatment. Treatment cycles are generally known and are about 1-28 days, generally about 7 days or about 1 between cycles.
Four-day drug holidays are frequently alternated. The treatment cycle may be continuous in other embodiments.

In some embodiments, the forms or compositions disclosed herein are formulated for oral administration using a pharmaceutically acceptable carrier. Pharmaceutical compositions formulated for oral administration are in the form of tablets, pills, capsules, cashiers, sugar-coated tablets, dragees, liquids, gels, syrups, slurries, elixirs, suspensions, or powders. Can be.

Pharmaceutically acceptable carrier The term "carrier" is a diluent or filler administered with a compound, a disintegrant, an anti-sedimentant,
Refers to surfactants, flow promoters, binders, lubricants, antioxidants, and other excipients and vehicles. Carriers are generally referred to herein as well as "Remington's Pharmaceu" by EW Martin.
It is described in "tical Sciences". Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethyl cellulose, sodium carboxymethyl cellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctacosanyl. Hydroxystearate, Hydroxypropyl Cellulose, Hydroxypropyl Cellulose, Hydroxypropyl Methyl Cellulose, Lactose, Lactose Monohydrate, Magnesium Stearate, Mannitol, Microcrystalline Cellulose, Poroxamer 124, Poroxamer 181, Poroxamar 182
, Poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. However, the carrier selected for the pharmaceutical composition provided in the disclosure of the present invention, and the amount of such carrier in the composition, is the method of formulation (eg, dry granulation formulation, solid dispersion). Please understand that it can change depending on the liquid formulation).

The term "diluent" or "filler" generally refers to a substance used to dilute a compound of interest prior to delivery. Diluents can also serve to stabilize the compound. Examples of diluents are starch, sugar, disaccharide, sucrose, lactose, polysaccharide, cellulose, cellulose ether, hydroxypropyl cellulose, sugar alcohol, xylitol, sorbitol, martitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, lactose. , Lactose monohydrate, dicalcium phosphate, cellulose, sucrose, dihydrated calcium phosphate, mannitol, microcrystalline cellulose, and tribasic calcium phosphate.

The term "disintegrant" generally refers to a substance that, upon addition to a solid preparation, promotes its decomposition or disintegration after administration, releasing the active ingredient as efficiently as possible and allowing its rapid dissolution. Examples of disintegrants include corn starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, processed corn starch, carboxymethyl sodium starch, povidone, pregelatinized starch,
And alginic acid.

The term "precipitation inhibitor" generally refers to a substance that prevents or inhibits the precipitation of an activator. One example of an anti-sedimentant is hydroxypropyl methylcellulose.

The term "surfactant" generally refers to a compound that reduces surface tension between two liquids or between a liquid and a solid. Examples of surfactants include poloxamers and sodium lauryl sulfate.

The term "fluidity accelerator" is commonly used in tablet and capsule formulations.
A substance that improves the flow characteristics during tablet compression and provides an anti-solidification effect. Examples of flow promoters are colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives,
And bentonite can be mentioned.

The term "binder" generally refers to any pharmacy that can be used to bind an active component and an inert component of a carrier together to maintain a sticky and discrete moiety together. Refers to a membrane that is generally acceptable. As an example of a binder, hydroxypropyl cellulose,
Hydroxypropyl methylcellulose, povidone, copovidone, ethyl cellulose, gelatin, and polyethylene glycol can be mentioned.

The term "lubricant" generally refers to a substance that, by addition to a powder blend, prevents a mass of compressed powder from sticking to the device during the tableting or encapsulation process. Lubricants can assist in the release of tablets from the die and can improve powder flow. Examples of lubricants include magnesium stearate, stearic acid, silica, fat, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc, and fatty acids containing _{lauric acid, oleic acid, and C 8} / C _{10 fatty acids.} Solubilizers can be mentioned.

The term "antioxidant" generally refers to a substance that inhibits the oxidation of other substances. In certain embodiments of the invention, an antioxidant is added to the pharmaceutical composition. Examples of antioxidants include ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid disodium salt, sodium sulfite, sodium metabisulfite, sodium hydrogen sulfite, butylated hydroxytoluene (BHT),
Butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, thioglycerol, thioglycolic acid, tocopherol (vitamin E), D-α tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and propyl gallate. be able to. In certain embodiments, the antioxidant is propyl gallate. In one embodiment, the pharmaceutical composition comprises CYT-0387 dihydrochloride monohydrate form II and an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), ascorbic acid, and propyl gallate. include. In certain embodiments, the pharmaceutical composition comprises CYT-0387 dihydrochloride monohydrate form II and an antioxidant, which is propyl gallate.

Antioxidants or antioxidants may be present in an amount sufficient to prevent, inhibit, and / or reduce the degradation of the active ingredient (eg, CYT-0387 Form II). As an example, the antioxidants are about 0.001%, about 0.002%, about 0.005%, about 0.01%, about 0.0.
It may be present in an amount of 2%, about 0.05%, about 0.1%, about 0.2%, about 0.5%, or about 1%. In one embodiment, the pharmaceutical composition is propyl gallate in an amount of about 0.001%, about 0.01%, about 0.1%, about 0.2%, about 0.5%, or about 1%. including. In some embodiments, the pharmaceutical composition comprises CYT-0387 dihydrochloride monohydrate form II and about 0.2% propyl gallate.

In certain embodiments, at least one active agent (including, for example, CYT-0387 dihydrochloride monohydrate form II), and (a)-(e): a) at least one diluent; b) at least. Provided are pharmaceutical compositions comprising one disintegrant; c) at least one fluidity enhancer; d) at least one lubricant; and e) one or more of at least one antioxidant.

In some embodiments, the pharmaceutical composition comprises at least one or at least two diluents. In certain embodiments, the pharmaceutical composition comprises one or two diluents. In certain embodiments, the diluents are mannitol, microcrystalline cellulose, lactose, glucose, sucrose, ludiflash, F-melt, advanced, Gale.
It is selected from the group consisting of nIQ, or any mixture thereof. In one embodiment, the diluent is mannitol, microcrystalline cellulose, or a mixture thereof.

In some embodiments, the pharmaceutical composition comprises at least one disintegrant. In certain embodiments, the pharmaceutical composition comprises one disintegrant. In certain embodiments, the disintegrant is sodium starch glycolate. In one embodiment, the disintegrant is croscarmellose sodium. In another embodiment, the disintegrant is crospovidone.

In some embodiments, the pharmaceutical composition comprises at least one flow enhancer. In certain embodiments, the pharmaceutical composition comprises one flow enhancer. In one embodiment, the flow accelerator is colloidal silicon dioxide.

In some embodiments, the pharmaceutical composition comprises at least one lubricant. In certain embodiments, the pharmaceutical composition comprises one type of lubricant. In one embodiment, the lubricant is magnesium stearate (stereate).

In certain embodiments, the pharmaceutical composition comprises CYT-0387 dihydrochloride monohydrate form II, at least one diluent, at least one disintegrant, at least one flow enhancer, at least one. Includes lubricants and at least one antioxidant. In a further embodiment
At least one diluent is microcrystalline cellulose, at least one disintegrant is sodium starch glycolate, at least one flow accelerator is colloidal silicon dioxide, and at least one lubricant. Is magnesium stearate and at least one antioxidant is propyl gallate. In a further embodiment, at least one diluent is lactose, at least one disintegrant is sodium starch glycolate, at least one flow accelerator is colloidal silicon dioxide, and at least one. The lubricant is magnesium stearate and at least one antioxidant is propyl gallate.

In other embodiments, the pharmaceutical composition comprises CYT-0387 dihydrochloride monohydrate form II, at least two diluents, at least one disintegrant, at least one flow enhancer, at least one. Includes lubricants and at least one antioxidant. In yet another embodiment
At least two diluents are microcrystalline cellulose and lactose, at least one disintegrant is sodium starch glycolate, at least one flow accelerator is colloidal silicon dioxide, and at least one gliding. The swamp is magnesium stearate and at least one antioxidant is propyl gallate.

In certain embodiments, the pharmaceutical composition comprises CYT-0387, of which at least about 80% is CYT-0387 dihydrochloride monohydrate form II. In a further embodiment
The pharmaceutical composition comprises CYT-0387, of which at least about 85% is CYT-0387.
Dihydrochloride monohydrate form II. In a further embodiment, the pharmaceutical composition is CYT-0.
387, of which at least about 90% is CYT-0387 dihydrochloride monohydrate form I
I. In a further embodiment, the pharmaceutical composition comprises CYT-0387, of which at least about 95% is CYT-0387 dihydrochloride monohydrate form II. In certain embodiments, the pharmaceutical composition comprises CYT-0387, of which at least about 97% is CYT-.
0387 Dihydrochloride monohydrate form II. In other embodiments, the pharmaceutical composition is CYT-0.
387, of which at least about 98% is CYT-0387 dihydrochloride monohydrate form I
I. In yet another embodiment, the pharmaceutical composition comprises CYT-0387, of which at least about 99% is CYT-0387 dihydrochloride monohydrate form II. In yet another embodiment, the pharmaceutical composition comprises CYT-0387, of which at least about 99.5% is CYT-0387 dihydrochloride monohydrate form II. In certain embodiments, the pharmaceutical composition comprises CYT-0387, of which at least about 99.9% is CYT-0387 dihydrochloride monohydrate form II.

The pharmaceutical composition comprises the pharmaceutically acceptable carriers detailed herein as if any combination of pharmaceutically acceptable carriers were listed specifically and individually. Please understand that.

Unit Dosage Form In some embodiments, the pharmaceutical compositions described herein are formulated in a unit dosage form. The term "unit dosage form" refers to physically separate units suitable as unit doses for a subject (eg, a human subject and other mammals), each unit, along with a suitable pharmaceutical carrier. Contains a predetermined amount of active material calculated to provide the desired therapeutic effect.

In a further embodiment, the invention is directed to a unit dosage form comprising CYT-0387 dihydrochloride monohydrate form II. In some embodiments, the unit dosage form is from about 10 mg to about 1000 mg.
, About 10 mg to about 800 mg, about 10 mg to about 700 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 1
0 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 10
mg to about 50 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 m
g ~ about 700 mg about 50 mg ~ about 500 mg, about 50 mg ~ about 400 mg, about 50 mg ~
About 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg
~ About 800 mg, about 100 mg ~ about 700 mg About 100 mg ~ about 500 mg, about 100 m
g ~ about 400 mg, about 100 mg ~ about 300 mg, about 100 mg ~ about 250 mg, about 10
0 mg to about 200 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, about 150 mg to about 200 mg, about 200 mg to about 300 mg, about 200 mg to about 250 mg
, Or in an amount corresponding to about 200 mg to about 300 mg of CYT-0387 free base.
-0387 Dihydrochloride monohydrate contains Form II.

In an additional embodiment, the dosage form is about 100 mg of CYT-0387 free base, about 150 m.
g CYT-0387 free base, 200 mg CYT-0387 free base, about 250 mg
CYT-0387 Free Base, 300 mg CYT-0387 Free Base, Approximately 400 mg CYT-0387 Free Base, or CYT-0387 Dihydrochloride Monohydrate Form II in an amount equivalent to approximately 500 mg CYT-0387 Free Base. including. In certain embodiments, the unit dosage form comprises CYT-0387 dihydrochloride monohydrate Form II in an amount corresponding to approximately 50 mg of CYT-0387 free base. In other embodiments, the unit dosage form is about 100 mg of CYT-0.
CYT-0387 Dihydrochloride monohydrate form II is contained in an amount corresponding to 387 free bases. In yet another embodiment, the unit dosage form comprises CYT-0387 dihydrochloride monohydrate form II in an amount corresponding to about 150 mg of CYT-0387 free base. In yet another embodiment, the dosage form comprises CYT-0387 dihydrochloride monohydrate Form II in an amount corresponding to about 200 mg of CYT-0387 free base. In certain embodiments, the dosage form is about 250 mg of CYT-03.
CYT-0387 Dihydrochloride monohydrate form II is included in an amount corresponding to 87 free bases. In a further embodiment, the dosage form is CY in an amount corresponding to about 300 mg of CYT-0387 free base.
Includes T-0387 Dihydrochloride Monohydrate Form II. In a further embodiment, the dosage form comprises CYT-0387 dihydrochloride monohydrate Form II in an amount corresponding to about 400 mg of CYT-0387 free base. In a further embodiment, the dosage form is about 500 mg CYT-038.
CYT-0387 Dihydrochloride monohydrate form II is contained in an amount corresponding to 7 free bases. In another embodiment, the pharmaceutical composition is CY in an amount corresponding to about 300 mg of CYT-0387 free base.
T-0387 Dihydrochloride monohydrate is a tablet in a dosage form containing Form II.

In a further embodiment, the invention presents 300 mg of the free base N- (cyanomethyl) -4-.
200 mg, providing a pharmacokinetic profile substantially similar to the dosage form comprising CYT-0387 dihydrochloride anhydrous form I in an amount corresponding to (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide. Free base N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) CYT-0 in an amount equivalent to benzamide
387 Dihydrochloride monohydrate Dosage forms containing Form II are targeted.

In certain embodiments of the invention, the unit dosage form comprises at least one pharmaceutically acceptable carrier. In other embodiments, the unit dosage form is CYT-0387 dihydrochloride monohydrate form I.
I, at least two diluents, at least one disintegrant, at least one flow enhancer,
It contains at least one lubricant and at least one antioxidant. In a further embodiment, the unit dosage form is about 36% to 44% CYT-0387 dihydrochloride monohydrate Form II.
About 44% to 58% diluent; about 4% to 8% disintegrant, about 0.25% to 0.75% flow enhancer, about 1.2% to 1.8% lubricant , And contains about 0.1% to 0.5% antioxidant. In yet another embodiment, at least two diluents are microcrystalline cellulose and lactose, at least one disintegrant is sodium starch glycolate, and at least one fluidity accelerator is colloidal silicon dioxide. Yes, at least one lubricant is magnesium stearate and at least one antioxidant is propyl gallate. In a further embodiment, the unit dosage form is about 36% to 44% CYT-0387 dihydrochloride monohydrate form II; about 30% to 38% microcrystalline cellulose; about 14% to 20%. Lactose, about 4% to 8% sodium starch glycolate, about 0.25% to 0.75% colloidal silicon dioxide, about 1.2% to 1.8% magnesium stearate, and about 0.1. Contains% to 0.5% propyl phosphate.

Preparation of Pharmaceutical Compositions The pharmaceutical compositions described herein can be prepared by any conventional method, eg, but not limited to, mixing.
It can be produced using methods of dissolution, granulation, dragee preparation, crushing, emulsification, encapsulation, entrap, melt spinning, spray drying, or lyophilization.

Those skilled in the art will recognize suitable methods and techniques for preparing tablets by conventional formulation. Illustrative methods and techniques for preparing powders for compression into tablets include dry or wet granulation. Dry granulation generally refers to the process of forming granules without the use of a liquid solution, whereas wet granulation generally refers to the process of adding a liquid solution to a powder for granulation.

Kits Kits containing the compounds of the formulas of this application or pharmaceutically acceptable salts thereof, isomers, prodrugs, or solvates, and suitable packages are also provided herein. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit
Compounds of the formulas described herein or pharmaceutically acceptable salts thereof, isomers, prodrugs,
Alternatively, it comprises a solvate and a label and / or instructions for using the compound in the treatment of an indication including the diseases or conditions described herein.

Products containing any compound of the formula described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof in a suitable container are also provided herein. Containers can be vials, bottles, ampoules, prefilled syringes, and IV bags.

Methods of Treatment The CYT-0387 form of the invention is a JAK kinase-related disease, eg, immunological and inflammatory diseases including organ transplantation; hyperproliferative diseases including cancer and myeloid proliferative diseases; viral diseases; metabolism. It can be used in the treatment of kinase-related disorders, including sexual disorders; and vascular disorders and the like.

In addition to primates such as humans, the compounds, compositions and methods of the invention can be used to treat a variety of other mammals. For example, but not limited to cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other cow species, sheep species, horse species, dog species, cat species, rodent species. Alternatively, mammals, including murine seeds, can be treated. However, the invention can also be practiced in other species such as birds (eg chickens).

The term "administer" should be considered to mean providing a compound of the invention to a subject in need of treatment.

The term "treat" or "treatment" refers to obtaining the desired pharmacological and / or physiological effect. The effect can be prophylactic in the sense of preventing the disease completely or partially, and / or therapeutic in the sense of partial or complete cure for the disease and / or the adverse effects caused by the disease. Treatment can cover any treatment of the disease in mammals and may be susceptible to the disease, but to prevent the disease from occurring in subjects who have not been diagnosed with the disease, the disease. Includes inhibiting, i.e. suppressing its onset, or alleviating the disease, i.e. causing regression of the disease. Therapeutic agents can be administered before, during or after the onset of the disease. Treatment of ongoing diseases, in which treatment stabilizes or reduces adverse clinical symptoms in patients, is of particular interest. Expected progression-free survival can be measured from month to year, depending on the number of recurrences, stage of disease, and prognostic factors, including other factors. Life extension is not limited, but at least 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 1 year, at least about 2 years, at least about 3 years, or more. Including time. Overall survival can also be measured from month to year. The patient's symptoms are
It may remain fixed or lowered.

The term "effective amount" refers to an amount that can be effective in deriving the desired biological or medical response, such as when administered to a subject to treat a disease. Includes an amount of compound sufficient to carry out the appropriate procedure. The effective amount depends on the compound, the disease and its severity, the age and weight of the subject to be treated, and the like. The effective amount can include a series of amounts.

The term "kinase-related disease", directly or indirectly, refers to abnormal kinase activity, especially J.
Refers to a disorder (s) resulting from or exacerbating AK activity and / or being relieved by inhibition of one or more of these kinase enzymes.

In a preferred embodiment, the kinase-related pathology is JAK kinase, JAK1, JAK2,
It is related to one or more of JAK3 or TYK2. In a particularly preferred embodiment, the disease is associated with JAK2 kinase. Such diseases include, but are not limited to, those listed in the table below.

The term "immunological and inflammatory disease" refers to immunological, inflammatory or autoimmune disease.
Rheumatoid arthritis, polyarthritis, rheumatoid spondylitis, osteoarthritis, gout, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Mucocolitis, ulcerative colitis, ulcerative colitis, Crohn's disease, autoimmune thyroid disorders, gastric inflammation, esophagitis, hepatitis, pancreatitis, nephritis, psoriasis, eczema, acne vulgaris,
Dermatomyositis, rash, multiple sclerosis, Alzheimer's disease, motor neuron disease (Rugerick's disease), Paget's disease, sepsis, conjunctivitis, nasal catarrh (neranl catarrh), rheumatoid arthritis, systemic systemic inflammatory reaction syndrome (SIRS), Polymyositis, dermatomyositis (DM), nodular polyarteritis (Polaritis nodoa) (PN), mixed connective tissue disease (MCTD), Schegren syndrome, Cruzon syndrome, chondropathy, systemic lupus erythematosus, strong skin disease , Vasculitis, lethal osteodysplasia, insulin resistance, type I diabetes and complications of diabetes and metabolic syndrome, but are not limited to these.

As the term "hyperproliferative disorder", cancer and myeloid proliferative pathologies, such as, but not limited to, cell proliferative pathologies: heart: sarcoma (angisarcoma, fibrosarcoma, rhabdomyosarcoma, lipoma). Sarcoma), mucinoma, rhabdomyosarcoma, fibrosarcoma, lipoma and teratoma; lung: bronchiogenic lung cancer (
Squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiole) carcinoma,
Bronchial adenomas, sarcomas, lymphomas, chondromatous hanlartoma, inesothelioma; gastrointestinal tract: esophagus (squamous epithelial cancer, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (
Cancer, lymphoma, leiomyosarcoma), pancreas (adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor,
Kaposi sarcoma, smooth myoma, hemangiomas, lipomas, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenocarcinoma, choriocarcinoma, teratoma, smooth myoma); urogenital organs: kidney (adenocarcinoma, Wilms tumor [renal] Sproutoma], lymphoma, leukemia), bladder and urinary tract (flat epithelial cancer, transitional cell carcinoma, adenocarcinoma), prostate (prostrate) (adenocarcinoma, sarcoma), testis (sperm epithelioma, teratoma, fetal cancer, Teratoma, choriocarcinoma,
Sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma)
, Biliary tract cancer, hepatoblastoma, angiosarcoma, hepatocellular adenomas, hemangiomas; Reticulosarcoma), multiple myeloma, malignant giant cell tumor spondyloma, osteochondroma (osteochronfrorna) (extrachondrosarcomatosis),
Benign chondromas, chondromyxoids, chondromyxoids, osteoids and giant cell tumors; nervous system: skull (bone tumors, hemangiomas, granulomas, yellow tumors, osteoitis deformians), spinal cord Membrane (meningioma,
Meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymal cell tumor, germinoma [
Pine-fruit tumor], teratoma, teratoma, oligodendroglioma, Schwan cell tumor, retinal germinoma, congenital tumor), spinal cord neurofibroma, meningeal tumor, glioma, sarcoma); Family: Uterine (uterine body cancer), cervix (cervical cancer, pretumor cervical dysplasia), ovary (ovarian cancer [serocystic cystic adenocarcinoma, mucinous cystic adenocarcinoma, unclassifiable cancer], granulosa capsule Membrane cell tumor, Sertrireidich cell tumor, undifferentiated germinoma, malignant teratoma), genital area (squamous epithelial cancer, endodermal cancer, adenocarcinoma, fibrosarcoma, melanoma),
Vagina (clear cell cancer, squamous epithelial cancer, vegetative sarcoma [fetal type rhombocythemia]), oviduct (canceroma); blood system: blood (myelogenous leukemia [acute and chronic], acute lymphoblastic leukemia, Chronic myelogenous leukemia, multiple myelogenous syndrome, myelodysplastic syndrome), Hodgkin's disease, non-hodgkin's lymphoma [malignant lymphoma]; , Lipomas, hemangiomas, cutaneous fibrosis, keloids, psoriasis; adrenal: neuroblastoma; and myeloproliferative disorders such as true myelofibrosis (PV), primary myelofibrosis, thrombocythemia, essential Thrombocythemia (ET), idiopathic myelofibrosis (AMM) (also called idiopathic myelofibrosis (IMF)), chronic myelogenous leukemia (CML), systemic myelodysplastic syndrome (SM), chronic Neutral leukemia (CNL), myelofibrosis syndrome (MDS) and systemic obesity cell disease (
SMCD). In certain embodiments, the myelofibrosis disease is selected from polycythemia vera (PV), primary myelofibrosis, thrombocythemia, and essential thrombocythemia (ET). In one embodiment, the pharmaceutical compositions of the present application may be suitable for the treatment of myeloproliferative disorders, which include polycythemia vera (PV), primary myelofibrosis, thrombocythemia, and essential thrombocythemia. Selected from sexual thrombocythemia (ET). In some embodiments, the pharmaceutical compositions of the present application may be suitable for the treatment of primary myelofibrosis.

The term "vascular disease" is not limited to cardiovascular disease, hypertension, hypertension, hypercholesterolemia, hyperlipidemia, thrombotic disorders, stroke, Raynaud's phenomenon, POEMS syndrome, angina,
Ischemia, migraine, peripheral arterial disease, heart failure, restenosis, atherosclerosis, left ventricular hypertrophy,
Refers to diseases including myocardial infarction, ischemic diseases of the heart, kidneys, liver and brain, and pulmonary artery hypertension.

Preferred diseases for JAK2 selective inhibitors include immunological and inflammatory diseases such as autoimmune diseases such as atopic dermatitis, asthma, rheumatoid arthritis, Crohn's disease, psoriasis, etc.
Cruzon syndrome, chondropathy, systemic erythematosus, scleroderma, mixed connective tissue disease, vasculitis, lethal osteodysplasia and diabetes; hyperproliferative disorders such as cancer, such as prostate cancer, colon , Breast cancer, liver cancer, eg liver cancer, lung cancer, head and neck cancer, eg glioma, skin cancer, eg metastatic melanoma, leukemia, lymphoma, multiple myelofibrosis and myeloproliferative disorders, For example, true erythrocytosis (PV), myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis (AMM) (also called idiopathic myelofibrosis (IMF)) and chronic myelofibrosis. Leukemia (CML); as well as vascular diseases such as hypertension, hypertrophy,
These include stroke, Raynaud's phenomenon, POEMS syndrome, angina, ischemia, migraine, peripheral arterial disease, heart failure, restenosis, atherosclerosis and pulmonary arterial hypertension.

In other embodiments, the disease is a solid tumor. For example, solid tumors include, but are not limited to, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, Rectal cancer, liver cancer, kidney cancer, stomach cancer (stomach cance)
r), skin cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer (eg, neuroblastoma), brain tumor (eg, glioma, Includes undifferentiated oligodendroglioma, adult polymorphic glioblastoma, and adult undifferentiated stellate cell tumor), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is non-small cell lung cancer, small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, pancreatic cancer, prostate cancer, or breast cancer. be. In certain embodiments, the solid tumor is non-small cell lung cancer, colon cancer, pancreatic cancer, or breast cancer. In a further embodiment, the solid tumor is non-small cell lung cancer. In one embodiment, the solid tumor is metastatic non-small cell lung cancer (NSCLC). In some embodiments
Solid tumors are epidermal growth factor receptor (EGFR) mutated, EGFR tyrosine kinase inhibitor (TKI) untreated metastatic non-small cell lung cancer (NSCLC). As an example, the EGFR mutation may be an EGFR exon 19 deletion or an exon 21 (L858R) substitution mutation. In certain embodiments, the solid tumor is metastatic Carstenrat sarcoma oncogene oncogene homologue (KRAS) mutated non-small cell lung cancer (NSCLC). In a further embodiment, the solid tumor is colon cancer. In a further embodiment, the solid tumor is pancreatic cancer. In yet another embodiment, the solid tumor is metastatic pancreatic duct adenocarcinoma. In a further embodiment, the solid tumor is breast cancer.

In a further method of the invention, the form, including CYT-0387, or CYT-0387 dihydrochloride monohydrate form II, maintains or increases hemoglobin levels in subjects experiencing anemia or hypoglobin reduction. Used for. The target of anemia is
Has endogenous hemoglobin levels below normal levels for healthy subjects of the same age and gender. Acceptable or "normal" levels are now established in medical practice. Anemia is evident when the hemoglobin level is less than about 13.0 g / dL for a human adult male and the hemoglobin level is less than about 12.0 g / dL for a non-pregnant human adult female. If so, the deficiency is obvious. Hemoglobin level measurements are performed using established techniques. If the hemoglobin level is less than about 8.0 g / dL, it is clear that you are in a state of severe anemia.

In use, CYT-0387 is administered to an anemic subject in an amount effective to maintain or increase hemoglobin levels in the subject. Therefore, in treated subjects, administration of the drug has the minimal effect of inhibiting further reduction of hemoglobin levels. More preferably, administration of the drug has the effect of increasing hemoglobin levels in the subject.

Subjects of anemia for whom treatment with CYT-0387 is effective include those who have received or are receiving chemotherapy or radiation therapy, such as cancer patients. A wide variety of chemotherapeutic agents are known to result in reduced levels of functioning red blood cells. Similarly, C
Candidates for YT-0387 treatment are those suffering from hematological disorders, including hematological malignancies that result in or are associated with a decrease in red blood cell count. In embodiments, the subject to be treated is a subject with anemia associated with or resulting from a blood condition such as myelodysplastic syndrome. Myelodysplastic Syndrome (MDS) is a term used to describe a group of diseases characterized by ineffective hematopoiesis that results in blood cytopenia and hypercellular bone marrow. MDS has been customarily considered synonymous with "pre-leukemia" because of the high risk of conversion to acute myeloid leukemia (AML). The development of AML and the clinical consequences of cytopenia are the major causes of morbidity and mortality in MDS. Debilitating symptoms of MDS include fatigue, pallor, infection, and bleeding. Anemia, neutropenia, and thrombocytopenia are also common clinical signs of MDS. In other embodiments, the subject to be treated is
It is a subject having anemia associated with or resulting from other blood conditions such as other blood malignancies affecting red blood cells, aplastic anemia, anemia associated with chronic disease anemia.
Chronic anemia is a specific cancer, including lymphoma and Hodgkin's disease; autoimmune disease,
For example, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and polymyalgia rheumatica; long-term infections such as urinary tract infections, HIV and osteomyelitis; heart failure; and diseases such as chronic kidney disease. In addition, patients with anemia resulting from conditions associated with increased destruction, shortened red blood cell survival and spleen isolation can also benefit from CYT-0387 treatment. Therefore, patients suffering from these conditions can be treated to improve the condition of hemoglobin descent or deficiency.

In certain embodiments, the subject to be treated is the subject of anemia experiencing thalassemia. In other embodiments, the subject to be treated is a subject other than those experiencing thalassemia.

In embodiments, the CYT-0387 form of the invention, such as CYT-0387 dihydrochloride monohydrate form II, is administered to a subject diagnosed with a myeloproliferative disorder, such as a myeloproliferative neoplasm, thereby. , Improving the prognosis of the disease, and in embodiments, treating hemoglobin deficiency or reduction specifically associated with the disease. In other embodiments, the CYT-0387 form of the invention, such as CYT-0387 dihydrochloride monohydrate form II, is administered to an anemic subject other than the anemic subject diagnosed with myeloproliferative disorders. .. Treatable subjects in this class exhibit anemia unrelated to myeloproliferative disorders. In some embodiments, the CYT-0387 form of the present application, such as CYT-0387 dihydrochloride monohydrate form II, is administered to an anemic subject diagnosed with cancer.

"Myeloproliferative disorders" and "myeloproliferative neoplasms (MPN)", especially polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), are diverse but Relative overproduction of one or more cells of myelogenous origin, growth factor independent in
A range of biological, pathological and clinical features including colonization in vitro, extramedullary hematopoiesis, extramedullary hematopoiesis, splenomegaly and hepatic hypertrophy, and thrombotic and / or hemorrhagic predisposition. Is an interrelated group of pluripotent hematopoietic stem cell cloning disorders that share. An international working group for research and treatment of myeloproliferative neoplasms (IWG-MRT) has been established to delineate and define these conditions (eg Vannucchi et al., CA Cancer).
J. Clin., 2009, Vol. 59: pp. 171-191), the definitions of these diseases shall apply to the purposes herein. Subjects, especially human patients showing MPN and especially PMF, can be identified in the art using the IWG-MRT criteria described above.
Subjects "at risk" for a particular form of MPN are those with an early stage form of the disease, eg, their genetic markers, such as PV (> 95%), ET (60%) and P.
Subjects with JAK2V617F alleles and the like associated with MF (60%) may be included. Subjects are also considered "at risk" for MFN morphology if they have already manifested early-stage morphological symptoms. Therefore, subjects exhibiting MFN are at risk of post-PV and post-ET, both of which develop after MPN.

The response of MPN patients and especially PMF patients to CYT-0387 treatment is particularly high if these patients are selected for CYT-0387 treatment in accordance with the present invention based on one or more of the following criteria: Powerful:
i. JAK other than thalidomide, lenalidomide, pomalidomide, and CYT-0387
Previous treatment with a drug selected from 2 inhibitors;
ii. Clinical criteria to choose from one or both of the following: (1) small spleen size and (2) low percentage of circulating precursor cells;
iii. Biochemical marker criteria selected from one or more of the following: (1) EGF,
TNF-α, G-CSF, IFN-α, MIP-1β, HGF, MIG, and VEGF
Increased levels of at least one protein selected from; (2) decreased levels of eotaxin; and (3) at least one selected from EPO, hepcidin and BMP-2
Changes in seed protein levels.

The improved results of CYT-0387 treatment brought about by prior patient selection are manifested as a strong improvement in anemia and / or splenic response. An "anemic response" means that a patient who has been dependent on increased hemoglobin levels or blood transfusions is no longer dependent on blood transfusions. It is desirable to achieve a minimum increase in hemoglobin of 2.0 g / dL for a minimum of 8 weeks, which is the level of improvement identified in the International Working Group (IWG) diagnostic criteria. However, if the increase is small but hemoglobin is still medically significant, it is considered to be within the term "anemic response".

"Spleen response" means a reduction in the size of the patient's spleen when assessed by either palpation of the spleen, which was previously palpable, or diagnostic imaging during physical examination. do. The IWG diagnostic criteria are a minimum of 50% reduction in palpable splenomegaly (spleen enlargement) of the spleen, which is at least 10 cm at baseline (before treatment), or palpable spleen above 5 cm at baseline. It identifies that palpable splenomegaly (spleen enlargement) is no longer palpable. However, smaller reductions are also considered to be within the term "spleen response".

In one embodiment, the patient selected is a patient who has previously received medication. More specifically, the patients selected for the treatment of CYT-0387 are thalidomide (CAS No. 50-35-1) or derivatives thereof, especially lenalidomide (CAS No. 191732-72).
Includes patients who have been or are currently being treated in -6). Both of these drugs are used in the treatment of multiple myeloma and appear to show some benefit in patients suffering from myeloproliferative disorders. To gain the additional benefits of subsequent CYT-0387 treatment, patients are treated with thalidomide, lenalidomide or pomalidomide or similar agents, or the effects of these agents compared to the initiation of treatment with CYT-0387. Within a time frame sufficient to become apparent, one of these drugs will be treated. Patients who meet these criteria will experience a significant anemic response when subsequently treated with CYT-0387 compared to patients untreated with this medication. In a preferred embodiment, the CYT-0387 patient is a patient who is the target of pretreatment with lenalidomide.

Patients selected for CYT-0387 treatment are also JAKs other than CYT-0387.
Includes patients who have been or are being treated with inhibitors. Especially INCBO1842
Patients previously treated with a JAK inhibitor named 4 or a JAK inhibitor named TG101348 are more CYT-038 than patients previously not treated with such treatment.
It was found to have a prominent spleen response to 7 treatments. In a preferred embodiment, CY
Patients selected for T-0387 treatment are those who are subject to treatment with JAK inhibitors other than CYT-0387 and who are also transfusion-dependent. INCB
O18424 is administered in a dose-escalation manner from a starting dose of 15 or 20 mg po BID to a 5 mg BID to 25 mg BID. TG101348 is administered once daily
The maximum tolerated dose (MTD) is determined at 680 mg / day. J other than CYT-0387
AK inhibitors include any other JAK inhibitor, in particular other JAK inhibitors having a different JAK affinity, selectivity or binding site than CYT-0387. These properties can be determined using the JAK2 crystal structure and modeling techniques and activity assays described in US7593820, the entire disclosure of which is incorporated herein by reference. To gain the additional benefits of subsequent CYT-0387 treatment, patients will either be treated with another JAK2 inhibitor or the effect of that JA2 inhibitor will be apparent in the patient compared to the initiation of CYT-0387 treatment. You will be treated with such drugs in a time frame sufficient to become.

Patients selected for CYT-0387 treatment also include patients with altered levels of detectable protein markers. More specifically, patients with elevated levels of certain protein markers, including certain cytokines and chemokines, are CYT-03.
When treated with 87, significant benefits can be experienced with respect to the anemia and / or splenic response of these patients to CYT-0387 treatment. In embodiments, elevated levels of one or more of the following protein markers mean that the patient is a good candidate for CYT-0387 treatment:
(1) EGF, that is, epidermal growth factor, its mature form is Swiss-Prot designated P0.
Includes residues 971-1023 of the sequence having 1133;
(2) TNF-a, that is, tumor necrosis factor alpha, its maturation and lysed form, is Swi.
Includes residues 77-233 of the sequence having ss-Prot designation P01375;
(3) G-CSF, that is, granulocyte colony stimulating factor, its mature form is Swiss-P.
Includes residues 30-207 of the sequence with rot designation P09919;
(4) IFN-α, i.e. interferon alpha, includes a family of subtypes whose mature form is well known in the art;
(5) MIP-Iβ, a macrophage inflammatory protein 1-beta (currently also known as CC motif chemokine 4, or CCL4), its mature form is Swi.
Residues 24-92 or 26- of any of the sequences having the ss-Prot designation PI3236
Including 92;
(6) HGF, that is, hepatocyte growth factor, its mature form is Swiss-Prot designated P.
Based on the sequence with 14210, the alpha chain with residues 32-494 and the residue 49
Includes beta chains with 5-728;
(7) MIG, a monokine induced by gamma interferon (CXCL)
(Also now known as 9) is a family of chemotactic cytokines whose mature form comprises residues 23-125 of the sequence having Swiss-Prot designation Q07325;
(8) VEGF, vascular endothelial growth factor A, its mature form is Swiss-Prot
Includes residues 27-232 of the sequence having the designation PI5692.

Patients participating in CYT-0387 treatment are selected based on elevation at one or more levels of any of the markers mentioned above if these patients are initially selected.
Experience a significant splenic response. An elevated level is a level that exceeds the level in a normal subject.

Patients participating in CYT-0387 treatment can also experience a significant anemic response if these patients are initially selected based on reduced levels of protein eotaxin. Also known as an eosinophil chemotactic protein, Swiss-P
This protein contains CC residues 24-97 of a sequence having rot designation P51671.
Eosinophils in response to allergens by functioning through interaction with 3
s) Promote the accumulation of. This is a prominent feature of allergic inflammatory reactions.

Additional additional markers useful in selecting patients for CYT-0387 treatment include altered levels of EPO, hepcidin and BMP-2. CYT-0387
Another example of a marker useful in selecting a patient for treatment is the level of BMP-6.

Other markers can be used to monitor CYT-0387 treatment or dosing regimens. By way of example, such markers are, but are not limited to, Compound 3, Compound 4,
Compound 8, compound 10, compound 12, and compound 13 can be included. The levels of these markers can be detected by commonly used methods, such as those described in the examples of the present application.

The "level" of a given marker is considered to change, ie increase or decrease, if the level measured in a given patient differs to a statistically significant degree from the corresponding level of a normal subject. .. Desirably, CY is a patient who exhibits at least 0.05 or more significant, i.e., altered marker levels to the extent that a better p-value is obtained.
Selected as a candidate for T-0387 treatment. In embodiments, the p-value is at least 0.
It is 03, 0.02 or 0.01, and in a preferred embodiment, the p-value is at least 0.
009, 0.007, 0.005, 0.003, 0.001, or better.

The level of a given marker can be determined using an assay already established to detect the markers mentioned above. In an embodiment, this is achieved by extracting a biological sample, such as whole blood or a fraction thereof, such as plasma or serum, from a candidate patient. Then, if desired, the sample is processed to concentrate the marker of interest, and this concentrated or genuine sample, eg, a detectable ligand for the marker,
Assay using, for example, a labeled antibody that selectively binds to a marker. The amount of marker present in the sample can then be determined semi-quantitatively or quantitatively to obtain a value, which is then the reference value, which is the normal level for that marker in a healthy subject. Compare the values. As mentioned above, a difference in marker level sufficient to reach a p-value of at least 0.05 indicates a significant change in marker level, with an increase in that marker level (or a decrease in the case of eotaxin). ) Is CYT
-0387 Candidate for treatment.

Suitable candidates for CYT-0387 treatment are also certain clinical cases, including patients with relatively small size spleen and patients with elevated levels of circulating or peripheral blasts. Patients who meet the criteria. These patients respond particularly well to CYT-0387 treatment with respect to their splenic response. In one embodiment, the patient selected is a patient who has not yet progressed to transfusion dependence. Spleen enlargement is assessed by palpation. The size and volume of the spleen can also be measured with diagnostic images such as ultrasound, CT or MRI. The normal size of the spleen is about 11.0 cm in length at the head and tail.

Patients with a low percentage of circulating blasts are also suitable candidates for CYT-0387 treatment. Precursor cells are immature progenitor cells normally found in bone marrow and not in peripheral blood. Precursor cells usually become mature blood cells. A low percentage of circulating blasts is measured by cell morphology analysis of peripheral blood smears and multi-parameter flow cytometry and immunohistochemistry. ≧ 1% precursor cells are used as a prognostic factor.

The compounds according to this application can be used in combination with one or more additional therapeutic agents. The therapeutic agent can be in the form of a compound, antibody, polypeptide, or polynucleotide. Therapeutic agents include, but are not limited to, chemotherapeutic agents, immunotherapeutic agents, radiotherapy agents, antitumor agents, anticancer agents, antiproliferative agents, antifibrotic agents, antiangiogenic agents, therapeutic antibodies, or these. Any combination can be mentioned.

In one embodiment, the present application is as a combined preparation for simultaneous use, another use or continuous use in a method of treating a disease, disorder, or condition mediated by JAK, eg, in treatment. , The formulations described herein and additional therapeutic agents are provided. Therapeutic agents include Bruton's tyrosine kinase, spleen tyrosine kinase, apoptotic signaling kinase, Janus kinase, lysyl oxidase, lysyl oxidase-like protein,
Matrix metallopeptidase, bromodomain-containing protein, adenosine A2B receptor, isocitrate dehydrogenase, serine / threonine kinase TPL2, discoidin domain receptor, serine / threonine protein kinase, IKK, MEK, EGF
It can be a therapeutic agent that inhibits or modulates the activity of R, histone deacetylase, protein kinase C, or any combination thereof. In certain embodiments, the therapeutic agent is PI3K (PI3Kγ, PI3Kδ, PI3Kβ, PI3Kα, and / or pa.
Inhibitors (including n-PI3K), JAK (Janus kinase, JAK1, JAK2, and /
Or JAK3 inhibitor, SYK (spleen tyrosine kinase) inhibitor, BTK (Bruton's tyrosine kinase) inhibitor, A2B (adenosine A2B receptor) inhibitor, ACK (
Activated CDC kinase, including ACK1 inhibitor, ASK (including apoptotic signaling kinase, ASK1) inhibitor, Aurora kinase, BRD (including bromodomain-containing protein, BRD4) inhibitor, Bcl (B cell CLL / Lymphoma, Bcl-1
And / or Bcl-2) inhibitors, CAK (CDK activating kinase) inhibitors, C
aMK (Carmodulin Dependent Protein Kinase) Inhibitor, CDK (Including Cyclin Dependent Kinase, CDK1, 2, 3, 4, and / or 6) Inhibitor, CK (Including Casein Kinase, CK1 and / or CK2) Inhibition Agents, DDR (including dyscoidine domain receptors, DDR1 and / or DDR2) inhibitors, EGFR inhibitors, FXR (farnesoid x receptor) inhibitors, FAK (focal adhesion kinase) inhibitors, GSK (glycogen synthase kinase) Inhibitor, HDAC (Histon Deacetylase) Inhibitor, IDO
(Indoleamine 2,3-dioxygenase) inhibitor, IDH (including isocitrate dehydrogenase, IDH1) inhibitor, IKK (l-kappa-B kinase) inhibitor, KDM
5 (lysyl oxidase) inhibitor, LCK (lymphocyte-specific protein tyrosine kinase) inhibitor, LOX (lysyl oxidase) inhibitor, LOXL (lysyl oxidase-like protein, LOXL1, LOXL2, LOXL3, LOXL4, and / or LOXL5
Inhibitors (including), MTH (mutT homolog) inhibitors, MEK (mitogen-activated protein kinase kinase) inhibitors, matrix metalloproteinases (MMP, MMP2)
Inhibitors (including MMP9) and / or mitogen-activated protein kinase (MA)
PK) Inhibitor, PD-1 (Programmed Cell Death Protein 1) Inhibitor, PD-L1
(Programmed Death Ligand 1) Inhibitor, PDGF (Platelet Derived Growth Factor) Inhibitor, Phosphorylase Kinase (PK) Inhibitor, PLK (including Polo-like Kinase, PLK1, 2, 3) Inhibitor, Protein Kinase (PK, Protein) Inhibitors (including kinases A, B, C), ST
K (serine / threonine kinase) inhibitor, STAT (signal transduction and transcription) inhibitor, serine / threonine protein kinase inhibitor, TBK (tank binding kinase) inhibitor, TLR (Toll-like receptor modulator, TLR-1, TLR) -2, TLR-3, TL
R-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10
, TLR-11, TLR-12, and / or TLR-13) inhibitors, TK (tyrosine kinase) inhibitors, TPL2 (serine / threonine kinase) inhibitors, NEK9 inhibitors, Abl inhibitors, p38 kinase inhibitors Agents, PYK inhibitors, PYK inhibitors, c-Kit
Inhibitors, NPM-ALK inhibitors, Flt-3 inhibitors, c-Met inhibitors, KDR inhibitors,
TIE-2 inhibitor, VEGFR inhibitor, SRC inhibitor, HCK inhibitor, LYN inhibitor, F
YN inhibitors, YES inhibitors, chemotherapeutic agents, immunotherapeutic agents, radiotherapy agents, antitumor agents, anticancer agents, antiproliferative agents, antifibrotic agents, antiangiogenic agents, therapeutic antibodies, or these It can be selected from any combination. In some embodiments, the PI3K-δ inhibitor is ChemDra.
When named with w, it is (S) -2- (1-((9H-purin-6-yl) amino) propyl) -5-fluoro-3-phenylquinazoline-4 (3H) -one (5-). Fluoro-
3-Phenyl-2-[(1S) -1- (9H-purine-6-ylamino) propyl] quinazoline-4 (3H) -one), US Pat. No. 7,923,260. It can be synthesized by the method of. In certain embodiments, the SyK inhibitor is Che.
When named in mDraw, it is 6- (1H-indazole-6-yl) -N- (4-morpholinophenyl) imidazole [1,2-a] pyrazine-8-amine (6- (1H-indazole-6). -Il) -N- [4- (Morpholine-4-yl) Phenyl] Imidazo [1,
2-a] Pyrazine-8-amine), US Pat. No. 8,450,321
It can be synthesized by the method described in No. In other embodiments, the BTK inhibitor is Chem.
When named in Draw, (S) -6-amino-9- (1- (but-2-inoyl) pyrrolidine-3-yl) -7- (4-phenoxyphenyl) -7H-purine-8 (9H) -On (6-amino-9-[(3R) -1- (2-butinoyl) -3-pyrrolidinyl]
It can also be synthesized by the method of -7- (4-phenoxyphenyl) -7,9-dihydro-8H-purine-8-one), US Pat. No. 8,557,803. In certain embodiments, the MEK inhibitor is trametinib. In some embodiments, the EGFR inhibitor is erlotinib. In one embodiment, the pharmaceutical product of the present application can be used in combination with a PI3K inhibitor, a MEK inhibitor, a TBK inhibitor, an EGFR inhibitor, or a combination thereof. In additional embodiments, the formulations of this application can be used in combination with trametinib. In other embodiments, the formulations of this application can be used in combination with erlotinib.

Chemotherapeutic agents can be classified into, for example, the following groups according to their mechanism of action. Antimetabolites / anticancer agents such as pyrimidine analogs (floxuridin, capecitabine and cytarabine); antiproliferative / mitotic inhibitors which are related inhibitors including purine analogs, folic acid antagonists and natural products, eg Vinblastine (vinblastine, vincristine) and microtubes such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epotiron and navelbine, epipodophylrotoxins (e)
pidipodophyllotoxin (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil,
Cisplatin, cyclophosphamide, cytoxan, dactinomycin, daunorubicin,
Doxorubicin, epirubicin, ifosfamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide, eg Mycin (Actinomycin D), Daunorubicin, Doxorubicin (Adriamycin), Ifosfamide, Anthracycline, Mitoxantrone, Breomycin, Plicamycin (
Mitramycin) and mitomycin; enzymes (L-asparaginase that systemically metabolize L-asparagin and deplete cells that do not have the ability to synthesize their own asparagin); antiplatelet agents; antiproliferative / threaded Division-inhibiting alkylating agents such as nitrogen mustard cyclophosphamide and analogs, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkylnitrosourea (BCNU) and analogs, streptozotocin), trazen- Dacarbazine (dacarbazine) (
DTIC); antiproliferative / mitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxaliplatinim),
Carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide;
Hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, niltamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); thrombolytic agents (for example,
Tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; anti-migratory
ry) agent; anti-secretory agent (breverdin); immunosuppressant tacrolimus sirolimus azathioprine, mycophenorate; compound (TNP-470)
, Genistine) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blockers, nitrogen monoxide donors; antisense oligonucleotides; antibodies (trastuzumab, rituximab); cells Cycle Inhibitors and Differentiation Inducers (Tretinoin); Inhibitors, Topoisomerase Inhibitors (Doxorubicin (Adriamycin), Daunorbicin, Dactinomycin, Eniposide, Epirubicin, Etoposide, Idarubicin, Irinotecan and Mitoxantrone, Topotecan, Ilinotecan Camptothecin, corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpredonisolone (methy)
lpednisone, prednisone and prednisolone
ne)); Growth factor signaling kinase inhibitor; dysfunction inducers, toxins such as cholera toxin, lysine, pyogenic exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activator; Chromatin.

As used herein, the term "chemotherapeutic agent" or "chemotherapeutic" (or "chemotherapeutic" in the case of treatment with a chemotherapeutic agent) is any non-useful for the treatment of cancer. It is intended to include proteinaceous (ie, non-peptide) compounds. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbocon, meturedopa (me).
turedopa) and uredopa; altretamine (alfre)
Emilylumine and memylameramine, including tamine, triethylenemelamine
lamine), triethylene phosphoramide, triethylene thiophosphor amide and trimethylolpropane melamine; acetogenin (acetogenin)
In particular, bullatacin and bullatacin); camptothecin (including synthetic analogs topotecan); bryostatin; callystatin; CC-1065 (including its adzelesin, calzelesin and bizelesin synthetic analogs); cryptophycin (
In particular cryptophycin 1 and cryptophycin 8); drastatin; zuocalmycin (including synthetic analogs, KW-2189 and CBI-TMI); erutellobin; pancratistatin; sarkozynic
tiin); spongistatin; nitrogen mustard, such as chlorambucil, chlornaphazine, cholophosphamide, estramustin, ifosfamide, chlormethine, chlormethine oxide hydrochloride, melphalan, nobenbitin (novembichin), phenesterin.
ne), predonimustine, trophosphamide, urasyl mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as ediyne antibiotics (eg calikeamycin, especially calikeamycin gamma II and Calicaremycin Phi I1,
For example, Agnew, Chem. Intl. Ed. Engl, No. 33: 183-186
See page (1994); dynemicins, including dynemicin A; bisphosphonates, such as clodronic acid; esperamicin; and neocarzinostatin chromophores and related chromophores, ediyne antibiotics, chromophores (chr).
omomophore)), acracinomycin, actinomycin, anthramycin, azaserine, bleomycin, dactinomycin (cac)
tinomycin), carabicin (carabicin), carminomycin (car)
rninomycin), carzinofilin, chromomycin, dactinomycin, daunorubicin, detorbicin, 6-diazo-5-oxo-
L-norleucine, doxorubicin (morpholino-doxorubicin, cyanomorpholino-
Includes doxorubicin, 2-pyrrolino-doxorubicin and deoxyxorubicin)
, Epirubicin, esorbicin, idarubicin, marcellomycin, mitomycin, such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, pepromycin, potfilomycin, puromycin, keramycin, rodorubicin , Streptozotocin, tubersidine, ubenimex, dinostatin, sorbicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU);
Folic acid analogs such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamipulin, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine. Carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens,
For example, carsterone, dromostanolone propionate, epitiostanol, mepitiostane, test lactone; anti-adrenals, such as aminoglutethimide, mitotane, trilostane; folic acid supplement (replinisher)
), For example folinic acid; acegraton; aldophosphamide glycoside; aminolevulinic acid; enyluracil; amsacrine; hestrabcil (hestr)
abucil); bisantren; edaturaxate; defofamine; demecorcin; diaziquone; elformin (el)
formthine); elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoid,
For example, maytancin and ansamitecin; mitoguazone; mitoxanthrone; mopidamole; nitraclin; pentostatin; phenamet; viralubicine; rosoxanthrone; fluoropyrimidine; phoric acid; podophylphosphate; 2-ethylhydrazide; procarbazine; PSK®; razoxane; Ryzoxin; sizophyllan; spirogermanium; tenuazonic acid; triadicon; 2,2', 2''-tricurotriemilylamine; tricotecene (particularly T-2 toxin, verraculin A, vinorelbine A and anguidin); urethane; Bindesin; dacarbazine; mannomustin; mitobronitol; mitractor; pipobroman; gasitosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids, such as paclitaxel (registered trademark). (TAXOTIRE®); chlorambusyl; gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinorelbine; platinum; etoposide (VP-16); ifosphamide; Mitroxantrone; vancristine; vinorelbine (Navelbine®); novantron; teniposide; edatorexate; daunomycin; aminopterin; xelooda; ibandronate; CPT-11; topoisolamase Difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (
Fluorouracil, leucovorin and irinotecan), and pharmaceutically acceptable salts, acids or derivatives of any of the above. In the present application, one or more chemotherapeutic agents are used or included. For example, gemcitabine, nab-paclitaxel, gemcitabine / nab-paclitaxel, capecitabine, oxaliplatin, and capecitabine / oxaliplatin can be used with the formulations of the present application.

Chemotherapeutic agents are also defined as antihormonal agents that act to regulate or inhibit hormonal action on tumors, such as tamoxifen (including Nolvadex ™), raloxifene, droloxyfen, 4-hydroxytamoxifen, Trioxyfen, cheoxyfen, LY117018, onapriston, and toremifene (Faresto)
n®), such as anti-estrogens and selective estrogen receptor modulators (SERMs); inhibitors of the enzyme aromatase, which regulate estrogen production in the adrenal gland, eg, 4 (5) -imidazole, aminoglute. Tetimide, Megastrol Assetate (Megace®), Exemestane, Formestane, Fadrosol, Borozole (Riviser®), Letrozole (Femara®), and Anastrozole (Arimidex®). Trademarks)), etc .; as well as antiandrogens such as flutamide, niltamide, bicalutamide, leuprolide (leu)
Prohde), and goserelin; as well as pharmaceutically acceptable salts, acids or derivatives of any of the above.

As anti-angiogenic agents, retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATTIN®, ENDOSTATIN®, slamin, squalamin, metalloproteinase-1, tissue inhibitor, metalloproteinase (me).
Tissue inhibitor of talloproternase) -2, plasminogen activator inhibitor-1, plasminogen activator inhibitor (inhibitor) -2, cartilage-derived inhibitor, peptidoglycan (nab-peptidoglycan), platelet factor 4 , Protamine sulfate (Kurupane), sulfated chitin derivatives (prepared from zuwai crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporines such as proline analogs ((1-1-)
Azetidine-2-carboxylic acid (LACA), cis hydroxyproline, d, I-3,4
-Dehydroproline, thiaproline, alpha-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5- (4-pyridinyl)
-Modulator of matrix metabolism containing -2 (3h) -oxazolone; methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-serum, ch
imp-3, chymostatin, tetradeca sulfate beta-cyclodextrin (beta-c)
ycodextrin terradecaulfate), eponemycin; phenylin, sodium aurothiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpha (alpba) -2-antiplasmin, bisantren, lobenzalit disodium, n-2-carboxy Phenyl-4-chloroanthranil (c)
Disodium haloanthronic acid or "CCA", thalidomide; angiogenesis-suppressing steroid, carboxyaminoimidazole (cargboxinami)
Nolmidazole); include, but are not limited to, metalloproteinase inhibitors such as BB94. Other anti-angiogenic agents include the following angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoform, VEGF-C, H.
Antibodies to GF / SF and Ang-1 / Ang-2, preferably monoclonal antibodies, are mentioned. Ferrara N. And Alitalo, K. et al. "Clinical
application of angiogenic growth factors
and their inhibitors "(1999) Nature Medi
See cine Vol. 5, pp. 1359-1364.

Beta-aminopropionitrile as an anti-fibrotic agent
To Palreyman et al., Published October 23, 1990, on compounds such as trile (BAPN), as well as inhibitors of lysyl oxidase, and their use in the treatment of diseases and conditions associated with abnormal collagen deposition. "Inhi
US Pat. No. 4,965,2 entitled "bitors of lysyl oxidase"
No. 88; for compounds that inhibit LOX for the treatment of various pathological fibrous conditions,
"Anti-fibrotic" for Khagan et al., Published March 5, 1991.
agents and methods for inhibiting the a
activity of lysyl oxidase in in situ using a
DJacently positioned diamine analogue su
US Pat. No. 4,997,854, entitled "bustrate," (these are incorporated herein by reference) includes, but is not limited to, the compounds disclosed. A further exemplary inhibitor is the "Inhibitors of lysyl oxidase" for Patents, et al., Published July 24, 1990, for compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine. Titled US Pat. No. 4,943,593; and, for example, US Pat. No. 5,021,456; US Pat. No. 5,5059,714; US Pat. No. 5,120,764; US Pat. No. 5,182.
, 297; US Pat. No. 5,252,608 (2- (1-naphthyloxymethyl (na))
Phthyloxymemyl)) -3-fluoroallylamine); and US Patent Application No. 2004/0248871 (these are incorporated herein by reference). Also, as an exemplary antifibrinolytic agent, a primary amine that reacts with the carbonyl group at the active site of lysyloxidase, more specifically to produce a product that is stabilized by resonance after binding to the carbonyl. For example, the following primary amines: emylenemamine, hydrazine, phenylhydrazine and derivatives thereof, semicarbonyls, and urea derivatives, aminonitriles such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated. Alternatively, saturated haloamines such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamine and selenohomocysteine lactone can be mentioned. Also, the anti-fibrotic agent is a copper chelating agent that penetrates or does not penetrate cells. Illustrative compounds include indirect inhibitors such as compounds that block aldehyde derivatives derived from oxidative deaminoization of lysyl and hydroxylysyl residues by lysyl oxidase, such as thiol amines, especially D-penicillamine or analogs thereof. For example, 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl) dithio) butanoic acid, p-2-amino-3-methyl-
3-((2-Aminoethyl) dithio) butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl) dithio) butane sulfura
te), 2-acetamidoethyl-2-acetamidoethanethiol sulfanate (s)
ulphanate), sodium-4-mercaptobutane sulfinate (merca)
ptobutanesulfinate) trihydrates can be mentioned.

As an immunotherapeutic agent, therapeutic antibodies suitable for treating patients, such as avagobomab (ab)
agovomab), adecaturumab, aphtuzumab, alemtuzumab, altumomab, amatsuximab, anatsumomab (
anatumomab), alcitumomab, bavituximab, bectu
momab), bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, katsumakisomab,
Cetuximab, cetuximab, sixtumab, clivatuzumab, konaturumab, daratumumab, drozitsumab, durigotumab
ab), dusigitumab, detumomab
), Dasetsumab, darotuzumab, ecromeximab (ec)
romeximab), elotuzumab, encituximab,
Ertumaxomab, etaracizumab
ab), farietuzumab, ficl
atuzumab), figitumumab, frambotumab, futuximab, ganitumab, gemtuzumab, girentuximab (g)
irentuximab), glembatumumab, ibritumomab, igovomab, imgatuzumab
), Indatuzumab, Inotuzumab, Intetumumab (i)
ntetumumab), ipilimumab, iratumumab, labetsuzumab, lexatumumab, lintszumab, lorbotuzumab
), Lucatumumab, mapatumumab
), Matsuzumab, Miratsuzumab, Minretumomab, mitumomab, moxetumomab, narnatumab, naputumomab, nimotuzumab, nimotuzumab, nimotuzumab, nimotuzumab
uzumab), nofetumomab, okaratsuzumab (oc)
aratumab), ofatumumab, olaratumab, onatumab, oportuzumab
, Oregobomab, panitumumab, parsatsuzumab, patritumab, pemtumomab, pertuzumab, pintumumab, pritumumab, pritumumab
Rakotumomab, radretumab, rituximab, rituximab, robatumumab, satsumomab (s)
atumomab), sibrotuzumab, siltuximab,
Simtuzumab, solitomab, takatuzumab, taplitumomab, tenatsumomab, teprotumumum
Tiga tsuzumab, tositumomab, trastuzumab, tsucotuzumab
b), ubrituximab, veltuximab, bolsetsuzumab (
Vorsetuzumab), botumumab, saltumumab, obinutuzumab, CC49 and 3F8, but not limited to these. The exemplary therapeutic antibody can be further labeled with or combined with radioisotope particles such as indium In111, yttrium Y90, iodine I-131.

The present application also provides a method of treating a subject undergoing one or more standard therapies, such as chemotherapy, radiation therapy, immunotherapy, surgery, or a combination thereof. Thus, one or more therapeutic agents or inhibitors may be administered before, during or after the performance of chemotherapy, radiation therapy, immunotherapy, surgery or a combination thereof.

Other examples of chemotherapy treatment, including standard or experimental chemotherapy, are described below.
In addition, treatment of specific lymphomas is described in Cheon, B. et al. D. , Leonard, J. et al.
P. , "Monoclonal Antibody for B-Ce
ll Non-Hodgkin's Lymphoma "The New Englan"
d Journal of Medicine 2008, Vol. 359 (No. 6), 613
~ 626; and Wierda, W. et al. G. , "Current and Inves
titational Therapies for Patients with C
LL "Hematology 2006, pp. 285-294. An overview of lymphoma development patterns in the United States is described by Morton, L. et al. M. Et al. "Lymphoma
a Incidence Patterns by WHO Subtype in t
he United States, 1992-2001 "Blood 2006, 1
It is described in Volume 07 (No. 1), pp. 265-276.

Examples of immunotherapeutic agents include rituximab (eg, rituximab), alemtuzumab (eg, campus, mab campus), anti-CD19 antibody, anti-CD20 antibody, anti-MN-14 antibody,
Anti-TRAIL, anti-TRAIL DR4 and DR5 antibody, anti-CD74 antibody, apolizumab, bebasitumab, CHIR-12.12, epiratzumab (hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, ofatumumab , PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, human autotumor-derived HSPPC-96, and Bertzzumab.
Additional immunotherapeutic agents include the use of cancer vaccines based on the genetic makeup of tumors in individual patients, such as lymphoma, an example of a vaccine being GTOP-99 (MyVax).
(Registered trademark)).

Examples of chemotherapeutic agents are alvocidib, arbocidib, antineoplaston AS
2-1. Antineoplaston A10, antithymocyte globulin, amifostine trihydrate,
Aminocamptothecin, arsenic trioxide, betaaletin, Bcl-2 family protein inhibitors ABT-263, ABT-199, BMS-345541, bortezomib (Vel)
cade®), bryostatin 1, busulfan, carboplatin, campus-1H, CC-5103, carmustine, caspofungin acetate, clofarabine,
Cisplatin, cladribine (Leustarin), chlorambucil (Leukelan), curcumin, cyclosporine, cyclophosphamide (Cycloxan,)
Endoxan, Endoxana, Cyclostin), cytarabine, deniroykin diphtytox, dexamethasone, DT PACE, docetaxel, drastatin 10, doxorubicin (Adriamycin®, adliblastin, doxorubicin hydrochloride, enzamethauricin hydrochloride, enzamethausin) , Everolimus (RAD)
001), fenretinide, filgrastim, melphalan, mesna, flavopyridol, fludarabine (fludarabine), geldanamycin (17-AAG), ifosfamide,
Irinotecan hydrochloride, ixavepyrone, lenalidomide (Revlimid®,
CC-5013), Lymphokine-activated killer cells, melphalan, methotrexate,
Mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil,
Nelarabine, Oblimersen (Genasens) Oblimersen (GX15-070),
Oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, pegylated liposome doxorubicin hydrochloride, pegfilgrastim, pentostatin (Nipent),
Perifosin, prednisolone, prednisone, R-roscobitin (seliciclib (Se)
licilib), CYC202), recombinant interferon alpha, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoetin, rituximab, salgramostim, sildenafilcitrate, simvasstatin, silolimus, styrylsulfone , Tachlorimus, Tanespimycin, Temsirolimus (CCl-779), Salidamide, Therapeutic allogeneic lymphocytes, Thiotepa, Tipifarnib, Velcade® (bortezomib or PS-341), Vincristine (oncobin), Vincristine sulfate, Vinorelbine Tartezomib, vorinostat (SAHA), vorinostat, and FR (fludarabin, rituximab), CHOP
(Cyclophosphamide, doxorubicin, bincristin, prednison), CVP (cyclophosphamide, bincristin and prednison), FCM (fludarabin, cyclophosphamide, mitoxantron), FCR (fludarabin, cyclophosphamide, rituximab) , Hyper CVAD (multidivided cyclophosphamide, vincristin, doxorubicin, dexamethasone, methotrexate, citalabine), ICE (iphosphamide, carboplatin and etopocid), MCP (mitoxantron, chlorambusyl and prednisolone), R-CHOP (rituximab and CHOP) ), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab-
ICE), as well as R-MCP (R-MCP). For example, oxaliplatin can be used in combination with the formulation of this application.

Therapeutic treatment can be supplemented with or combined with any of the aforementioned treatments by transplantation of stem cells or treatment. An example of a modified approach is radioimmunotherapy in which a monoclonal antibody is combined with radioisotope particles such as indium-111, yttrium-Y90, and iodine-131. Examples of combination therapies are iodine-131 tositumomab (Bexxar®), yttrium-90 ibritumomab tiuxetan (Z).
Everin®), Bexxar® and CHOP, but are not limited to these.

Other treatment procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, systemic irradiation, stem cell injection, bone marrow resection with stem cell support, and in vitro treatment. Peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, pharmacological research, low LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and myeloid non-destructive allogeneic hematopoietic stem cell transplantation. Be done.

The present application provides the preparation alone or in combination with one or more therapeutic agents in the treatment of myeloproliferative and cancer. The application also treats the disease, comprising administering to a patient in need of the formulation described herein, including CYT-0387 dihydrochloride monohydrate form II in tablet form. If the disease is true erythrocytosis (PV), myeloid fibrosis, thrombocythemia, essential thrombocythemia (ET), pancreatic cancer, metastatic pancreatic ductal adenocarcinoma, breast cancer, Colon cancer, non-small cell lung cancer (NSCLC), and EGFR mutated, EGFR TKI untreated metastatic NSCLC and metastatic KRAS mutated NSCL
Also provided is a method selected from the group consisting of metastatic NSCLC, including C. In addition, the application applies to patients in need thereof the formulations described herein (CYT-0 in tablet format).
A method for treating a disease, comprising administering 387 dihydrochloride monohydrate form II) and optionally administering one or more therapeutic agents. Provided is a method in which the species or therapeutic agent is selected from the group consisting of trametinib, erlotinib, gemcitabine, nab-paclitaxel, oxaliplatin, capecitabine, or a combination thereof.

It is understood that the following examples exemplify certain aspects of the application. It is also understood that the values and parameters shown in the examples may be modified within reasonable variation and various variations may be made within the scope of the present application.

(Example 1)
Method of preparation N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) Benzamide (CYT-0387) can be synthesized as described in US Pat. No. 8,486,941 and PCT application WO2012 / 071612.

CYT-0387 Dihydrochloride Monohydrate Form II from CYT-0387 Anhydrous Form I
N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) A molar excess of hydrochloric acid in water was added to a suspension of benzamide (CYT-0387) dihydrochloride anhydrous form I in methanol. The resulting solid was isolated and washed with methanol and aqueous hydrochloric acid to produce CYT-0387 dihydrochloride monohydrate form II.

CYT-0387 Dihydrochloride Monohydrate from CYT-0387 Free Base Form II
N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) A molar excess of concentrated hydrochloric acid was added to a suspension of benzamide (CYT-0387) free base in methanol. N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) dihydrochloride monohydrate form II is optionally selected for the obtained suspension. And water was added. Optionally seeded N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide (CYT-0387) dihydrochloride monohydrate Form II is described above. Can be prepared as it is. The resulting solid is isolated, washed with methanol and aqueous hydrochloric acid, and CYT-0.
387 Dihydrochloride monohydrate Form II was produced.

CYT-0387 Monohydrochloride Anhydrous Form I from CYT-0387 Free Base
N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) To a suspension of benzamide (CYT-0387) free base in methanol was added 1.0 molar equivalent of concentrated hydrochloric acid. The resulting solid is isolated, washed with methanol and CYT-03.
87 Monohydrochloride Anhydrous Form I was produced.

CYT-0387 Anhydrous Monohydrochloride Form III from CYT-0387 Anhydrous Monohydrochloride Form I
The suspension of CYT-0387 monohydrochloride anhydrous form I is stirred in water / THF (30% water; v / v). The resulting solid was isolated and washed with a water / THF mixture to produce CYT-0387 monohydrochloride anhydrous form III.

CYT-0387 Dihydrochloride Monohydrate Anhydrous Form I from CYT-0387 Dihydrochloride Monohydrate Form II
II
Suspension of CYT-0387 dihydrochloride monohydrate form II in methanol / water (30% water; v
/ V) Stir in. The resulting solid is isolated, washed with a methanol / water mixture and CYT-
0387 Monohydrochloride Anhydrous Form III was produced.

The above embodiment is subjected to a powder X-ray diffraction pattern (XPPD) using the procedure described below.
), Differential scanning calorimetry (DSC), thermography analysis (TGA), and dynamic vapor adsorption (DVS).

Powder X-ray diffraction: XRPD analysis uses copper radiation (CuKα, λ = 1.5418 Å) with a diffractometer (PANanalytic XPERT-PRO, PANAanalytica)
l B. V. , Almelo, Netherlands). By depositing a powdered sample in the center of an aluminum holder with a zero background plate
A sample for analysis was prepared. The generator was operated at a voltage of 45 kV and an amperage of 40 mA. The slits used were Soller 0.02 rad, antidispersion 1.0 °, and divergence. The rotation speed of the sample was 2 sec. Scan at 2-40 ° 2θ for 15m
During in, the step size was 0.0167 ° 2θ. Data analysis is X'Per
tHighcore version 2.2c (PANNalytical B.V., Al
melo, Netherlands) and X'Pert Data Viewer Version 1
.. 2d (PANNalytical BV, Almelo, Netherlands)
Was carried out by.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) The XRPD pattern for benzamide dihydrochloride monohydrate Form II is shown in FIG.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) The XRPD pattern for benzamide monohydrochloride anhydrous form I is shown in FIG.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) The XRPD pattern for benzamide monohydrochloride anhydrous form III is shown in FIG.

XRPD peaks of various CYT-0387 forms are found in Table 1 above.

Differential scanning calorimetry: N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate The thermal properties of Form II are measured by differential scanning calorimetry (DSC). ) Equipment (TA Q1000, TA Instruments, New)
Castle, DE, USA) was used for evaluation. Approximately 5-10 mg of solid samples were placed in standard aluminum dishes with pinholes for each experiment and heated at a rate of 10 ° C./min under a nitrogen purge of 50 mL / min. Data analysis, Universal An
alysis 2000 version 4.7A (TA Instruments, New)
Castle, DE, USA) was used. Thermal analysis of fusion was performed by sigmoid integration of endothermic melting peaks.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) DSC for benzamide dihydrochloride monohydrate form II is shown in FIG.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-The DSC for benzamide monohydrochloride anhydrous form I is shown in FIG.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-The DSC for benzamide monohydrochloride anhydrous form III is shown in FIG.

Thermogravimetric analysis: Thermogravimetric analysis (TGA) of N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate form II was performed by the TGA apparatus (TGA). TAQ500, TA Instruments, New Castle,
It was carried out in DE, USA). Approximately 5-10 mg of solid sample was placed in an open aluminum dish for each experiment and heated at a rate of 10 ° C./min under a nitrogen purge of 60 mL / min. Data analysis, Universal Analysis 2000 version 4.7
A (TA Instruments, New Castle, DE, USA) was used.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) The TGA for benzamide dihydrochloride monohydrate Form II is shown in FIG.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) The TGA for benzamide monohydrochloride anhydrous form I is shown in FIG.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) The TGA for benzamide monohydrochloride anhydrous form III is shown in FIG.

Dynamic vapor adsorption: N- (cyanomethyl) -4- (2- (4-morpholinophenylamino))
Pyrimidine-4-yl) Benzamide Dihydrochloride Monohydrate Form II hygroscopicity, Dynamic Vapor Adsorption (DVS) Device (TGA Q5000 TA Instruments, New Ca)
It was evaluated at room temperature using stle, DE). Adsorption and desorption of water at room temperature 0-90
It was examined as a function of relative humidity (RH) over the% range. Moisture in the chamber was increased from the initial level of 50% RH to 60% RH and retained until the solid and atmosphere reached equilibrium. The equilibrium test was continued until it passed, otherwise it was completed after 10 hours. At this point, the RH increased by 10% and the process was repeated until it reached 90% RH and was equilibrated. During this period, water adsorption was monitored. For desorption, the relative humidity was reduced in a similar manner and the complete adsorption / desorption cycle was measured. All experiments, d
The equilibration endpoint was determined by operating in m / dt mode (mass variation over time). About 4 mg of solid CYT-0387 was used. Data analysis, Universal
l Analysis 2000 version 4.7A (TA Instruments,
New Castle, DE, USA) was used.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) Benzamide dihydrochloride monohydrate DVS for Form II is shown in FIG.

N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) benzamide (CYT-0387) dihydrochloride monohydrate Form II and N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide CYT-0387) hydrochloride Single crystal X-ray crystal structure analysis data for salt anhydrous form I is summarized in Table 2 below. Data from further characterization of the crystals are summarized in Table 3 below.

Microscopic images of various forms of the present invention can be viewed with an Olympus polarizing microscope (BX-51, Oly).
Obtained using mpus, Center Valley, PA, USA). Samples were dispersed in mineral oil and tested under cross-polarization using a 530 nm wave (results not shown).

^*0.75%粒内、0.75%粒外ステアリン酸Mg (Example 2)
CYT-0387 Dihydrochloride Monohydrate Form II, 100 mg, 150 mg, and 20
Tablets containing in an amount corresponding to 0 mg of CYT-0387 free base can be prepared by the methods described herein. CYT-0387 Dihydrochloride Monohydrate Form II, 100
Tablets were prepared containing mg, 150 mg, 200 mg, 250 mg, and 300 mg in amounts corresponding to the CYT-0387 free base. Table 4 below summarizes the formulation of such tablets.

^* 0.75% intragranular, 0.75% extragranular Mg stearate

The tablet preparation shown in Table 4 contains propyl gallate, which is CYT-03.
It reduced the degree or level of oxidative degradation of 87 Form II, resulting in increased stability of CYT-0387 Form II. This was determined from studies investigating the promising effects of different antioxidants on the inhibition or prevention of degradation of CYT-0387 dihydrochloride monohydrate form II. In early studies, five antioxidants with three different mechanisms of action were tested: free radical scavenger antioxidants (propyl gallate, butylated hydroxyanisole).
BHA), and butylated hydroxytoluene (BHT)), sacrificial reducing agent (ascorbic acid), and oxygen scavenger (sodium metabisulfite).

20 μg / mL CYT-0387 dihydrochlorid monohydrate in 70% (v / v) 50 mM acetate buffer (pH 4.0) and 30% (v / v) methanol Form I
Aqueous solutions containing I were incubated at 60 ° C. for up to 7 days in the absence (used as a control) and presence of 0.1% (w / v) antioxidant. On days 0, 5, and 7, Zorbox SB-C8 columns (Phenomenex, Torrance, CA).
The solution was analyzed using reverse phase HPLC with. 0.1% as shown in Table 7
The presence of propyl gallate, BHA, or ascorbic acid at the (w / v) level is CYT-0387 morphology II compared to BHT and sodium metabisulfite at the same level.
Inhibited or prevented the decomposition of. Less than 1 percent of CYT-0387 Form II was degraded in the presence of propyl gallate or BHA. For 0.1% ascorbic acid, all degradation products could not be determined due to interference, but no major oxidative degradation products were observed (data not shown).

In additional studies, the effects of lower concentrations of 0.01% and 0.001% (w / v) of propyl gallate, BHA, and ascorbic acid on the stability of CYT-0387 were tested under the same conditions. .. The results of these studies are summarized in Table 7. The result is 0.
It was shown that at 01% (w / v) antioxidant levels, increased stability of CYT-0387 Form II was observed at 60 ° C. for up to 7 days in the presence of propyl gallate or ascorbic acid. .. Moreover, at 0.001% (w / v) antioxidant levels, the presence of propyl gallate reduced or inhibited the degradation of CYT-0387 as compared to BHA and ascorbic acid (Table 7). These results showed that among the antioxidants tested, propyl gallate was the most effective in inhibiting or preventing the degradation of CYT-0387 dihydrochloride monohydrate form II.

^a 製剤中に存在した不純物を含む
^b N/A:入手不能

^a Contains impurities that were present in the formulation
^b N / A: Not available

Then, in the presence of 0%, 0.2%, 0.5%, or 1.0% propyl gallate, 25
CYT-0 at ° C / 60% RH (relative humidity) or 40 ° C / 75% RH for up to 6 months
The stability of the 100 mg tablet formulation containing 387 form II was tested. Degradation profiles were determined at 0, 1, 3, and 6 months. Table 8 summarizes the results of studies up to 6 months at 40 ° C./75% RH. The result is that the 100 mg tablet formulation of CYT-0387 Form II with 0.2% propyl gallate at 40 ° C./75% RH is 0%.
100 of CYT-0387 Form II with 0.5% or 1.0% propyl gallate
It was shown to exhibit increased stability compared to the mg tablet formulation. 25 ° C / 60% RH
The results of the study at CYT-0387 Form II showed that degradation was also reduced with propyl gallate at 0.2%, 0.5%, and 1.0% (data shown). do not have).
The observed tendency for degradation profiles at 25 ° C / 60% RH is 40 ° C / 75% R.
It was similar to that observed in H. That is, the increased stability of CYT-0387 Form II in the tablet formulation is 0.2% compared to 0%, 0.5%, and 1% propyl gallate.
Observed in propyl gallate (data not shown). Considering these together, these results show that among the antioxidants tested in these studies and their percentage, propyl gallate at 0.2% is in the form of CYT-0387 dihydrochloride monohydrate. It shows that it provided an optimal (optional) level of stability of II.

(Example 3)
CYT-0387 Dihydrochloride Monohydrate Form II (100, 150, 200, and 300)
A phase 1 single dose study of healthy subjects with tablets containing (dose equivalent to mg free base) and capsules containing CYT-0387 anhydrous form I of hydrochloride (dose equivalent to 300 mg free base). Evaluated in.

Intensive PK and PD sampling was performed 0.5 to 36 hours after administration. Safety was monitored throughout the study. Parametric difference analysis (ANOVA) using a mixed-effects model was used to fit the natural logarithmic transformation of _{PK parameters (AUC and C max).} 100 mg, 150 mg, 200 mg and 300 mg CYT-0387 dihydrochloride monohydrate form II tablets and 300 mg CYT-0387 dichloride using 70% to 143% equivalent boundaries for AUC and C _max. A 90% confidence interval was constructed for the ratio of the geometric mean to the hydrochloride anhydrous form I capsules. Pharmacokinetic data are shown in Table 5.

(Example 4)
CYT-0387 is a selective small molecule inhibitor of Janus kinases 1 and 2 (JAK1 / JAK2) currently under investigation for the treatment of myelofibrosis. This study included mass balance / recovery, metabolite profile, pharmacokinetics, of radiolabeled CYT-0387 in humans.
And the safety was evaluated.

Six healthy individuals (subjects) received a single oral dose of 200 mg of CYT-0387 containing ^{approximately 100 μCi of [14C] -CYT-0387.} Up to 21 days or 2
Blood samples were collected until the plasma radioactivity of two consecutive samples fell below the detection boundary or until urine and fecal sampling was interrupted. Urine / fecal samples up to 21 days or ≧ 90
% Was collected until collected in feces and urine, and radioactivity at two consecutive sampling intervals was ≤1% of the administered dose. LC-MS /
Plasma concentrations of CYT-0387 and metabolites were measured using MS and total radioactivity was assessed by liquid scintillation counting. Metabolite profiling was performed on selected urine, fecal, and plasma samples. A safety assessment was conducted throughout the study.

Results: CYT-0387 was well tolerated. No grade 3 or 4 AEs, SAEs, or AEs leading to study interruptions were reported. The most frequently reported AEs were dizziness, headache, and nausea. The highest concentration of drug-derived radioactivity in plasma was observed 2.5 hours after administration. The average concentration ratio between blood and plasma is 0.7 to 0 over the entire 24 hours after administration.
.. It is in the range of 9, showing a low association with radioactive blood cells. The total recovery rate of radioactivity is 9
It was 6.7% (feces: 69.3%; urine: 27.5%). The circulating radioactivity is mainly metabolites M21 (64.2%), CYT-0387 (17.3%), and metabolites (M8 :).
5.8%; metabolites M19: 5.2%; M5: 2.7%; M28: 2.5%; and M20
: 2.3%). The main component excreted in feces is CYT-0387 (dose 1).
2.6%) and other metabolites (M21: 12.7% of dose; co-eluting M19 / M33:
It was M14 (21.4% of the dose) with (7.1% of the dose). The remaining 10 identified metabolites in the faeces each accounted for less than 5% of the dose. In urine, the metabolite M21
It was the major species (11.5% of the dose) and low levels of trace metabolites were observed.

After oral administration in healthy subjects, [ ^14C ] -CYT-0387 was predominantly eliminated in faeces as a combination of metabolites and unchanged parent drug.

(Example 5)
CYT-0387 is a selective small molecule inhibitor of Janus kinases 1 and 2 (JAK1 / JAK2) and is currently under investigation for the treatment of myelofibrosis. First of patients with myelofibrosis
In a / 2-phase study, 300 mg of CYT-0387 capsules once daily was selected as the preferred benefit: phase 3 dose based on the risk profile. Immediate release tablet formulation (
CYT-0387 tablets) was developed for further clinical evaluation. The relative bioavailability of CYT-0387 tablets and capsules was evaluated in this study, CYT-038.
A phase 3 dose of 7 tablets was identified.

CYT-0387 tablets (100-300 mg) vs. capsules (300 mg) after a single dose
) Pharmacokinetics (PK) was evaluated in healthy subjects. CYT-0387 Tablets PK at doses above the therapeutic dose (400 and 800 mg) are also under feeding and fasting conditions.
And acid inhibitors (ie, omeprazole) were used for evaluation. Intensive PK sampling was performed up to 36 hours after administration. Safety was monitored throughout the study. A parametric analysis of variance (ANOVA) using a mixed-effects model was used to fit the natural logarithmic transformation of _{the PK parameters (AUC and C max).} Using 70% to 143% equivalent boundaries for AUC and C _max, against the geometric mean ratio of 100 mg, 150 mg, 200 mg and 300 mg CYT-0387 tablets PK to 300 mg CYT-0387 capsules. A 90% confidence interval was constructed. A similar approach was used to assess the effects of food and omeprazole.

200 mg CYT-0387 tablets provided plasma exposure equivalent to 300 mg CYT-0387 capsules (Table 6). CYT-0387 plasma exposure increased from 100 to 800 mg, which was lower than dose proportional. Eating a low-fat and high-fat diet, CYT-
For 0387 tablets C _max (38% and 28% increase for low-fat and high-fat diets, respectively) and AUC _inf (16% for low-fat and high-fat diets, respectively)
And 28% increase) increased moderately. Omeprazole reduced the exposure of CYT-0387 tablets by 36% for _{C max} and 33% for _{AUC inf.} These differences did not appear to be clinically relevant.

%CV=変動係数(%);CI=信頼区間;データは必要に応じて丸め、有効数字３桁として示されて
いる A 200 mg CYT-0387 tablet provides an exposure equivalent to a 300 mg CYT-0387 capsule. Plasma exposure of CYT-0387 tablets increased lower than the dose-proportional method. No clinically relevant effects of food or acid inhibitors were observed for CYT-0387 Tablets PK.

% CV = coefficient of variation (%); CI = confidence interval; data is rounded as needed and shown as 3 significant digits

(Example 6)
In this example, M14 (Compound 3), M8 (Compound 4), M20 (Compound 12), M21
(Compound 13), preparations of Compound 8 and Compound 10 have been described.

¹H NMR (400 MHz, DMSO-d₆): δ = 13.21 (s, 1H), 9.85 (s, 1H), 8.62
(d, J = 5.2 Hz, 1H), 8.28 (d, J = 8.2 Hz, 2H), 8.10 (d, J = 8.2
Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 5.2 Hz, 1H), 7
.33 (d, J = 9.0 Hz, 2H), 4.19 (s, 2H), 3.98 (m, 2H), 3.71 (m, 2H) 4- (2-Chloropyrimidine-4-yl) benzoic acid (3.0 g, 12.8 m) in a flask
mol), 4-morpholonoaniline (2.7 g, 14.0 mmo)
l, 1.1 eq), and NMP (30 mL) were charged. The resulting solution was stirred at 120 ° C. Upon completion, the reaction was cooled and 30 mL of aqueous NaHCO ₃ was added. The resulting slurry is filtered, rinsed with water and dried under vacuum at 45 ° C. to have the following structure 4
-(2-((4- (3-oxomorpholino) phenyl) amino) pyrimidine-4-yl)
Obtained benzoic acid (Compound 3):

^{1 1} H NMR (400 MHz, DMSO-d ₆ ): δ = 13.21 (s, 1H), 9.85 (s, 1H), 8.62
(d, J = 5.2 Hz, 1H), 8.28 (d, J = 8.2 Hz, 2H), 8.10 (d, J = 8.2
Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 5.2 Hz, 1H), 7
.33 (d, J = 9.0 Hz, 2H), 4.19 (s, 2H), 3.98 (m, 2H), 3.71 (m, 2H)

¹H NMR (400 MHz, DMSO-d₆): δ = 9.83 (s, 1H), 8.81 (t, J = 6.0 Hz
, 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.27 (d, J = 8.5 Hz, 2H), 8.05
(d, J = 8.4 Hz, 2H), 7.85 (d, J = 6.9 Hz, 2H), 7.51 (d, J = 4
.8 Hz, 1H), 7.41 (bs, 1H), 7.32 (d, J = 8.9 Hz, 2H), 7.06 (bs, 1H
), 4.19 (s, 2H), 3.98 (m, 2H), 3.85 (d, J = 5.8 Hz, 2H), 3.72 (m,
2H)；ＨＲＭＳ（ＥＳＩ＋）：Ｃ_２３Ｈ_２３Ｎ_６Ｏ_４［Ｍ＋Ｈ］^＋の計算値：４４７．
１８、実測値：４４７．１９。 In a flask, compound 3 (1.0 g, 2.43 mmol), TBTU (1.0 g, 3.1)
5 mmol, 1.3 eq), glycinamide hydrochloride (0.32 g, 1.2 eq), DMS
It was loaded with O (9 mL) and i-Pr ₂ NEt (0.65 g, 2.92 mmol, 1.2 eq). When the reaction is complete, water (7.7 mL) is added and the resulting slurry is filtered.
Rinse with DMSO / water (2: 1) and water. The isolated solid is reslurried in 10 mL of MeOH, filtered, washed with MeOH and dried in a vacuum oven at 45 ° C. to have the following structure: N- (2-amino-2-oxoethyl)- 4- (2-((4- (3-oxomorpholino) phenyl) amino) pyrimidin-4-yl) benzamide (Compound 4) was obtained:

^{1 1} H NMR (400 MHz, DMSO-d ₆ ): δ = 9.83 (s, 1H), 8.81 (t, J = 6.0 Hz)
, 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.27 (d, J = 8.5 Hz, 2H), 8.05
(d, J = 8.4 Hz, 2H), 7.85 (d, J = 6.9 Hz, 2H), 7.51 (d, J = 4)
.8 Hz, 1H), 7.41 (bs, 1H), 7.32 (d, J = 8.9 Hz, 2H), 7.06 (bs, 1H)
), 4.19 (s, 2H), 3.98 (m, 2H), 3.85 (d, J = 5.8 Hz, 2H), 3.72 (m,
2H); HRMS (ESI +): C ₂₃ H ₂₃ N ₆ O ₄ [M + H] ⁺ calculated value: 447.
18, measured value: 447.19.

¹H NMR (300 MHz, DMSO-d₆): δ 4.36 (d, J = 5.5 Hz, 2H), 8.05 (m,
J = 8.5 Hz, 2H), 8.24 (d, J = 5.3 Hz, 1H), 8.32 (m, J = 8.5 Hz,
2H), 8.89 (d, J = 5.2 Hz, 1H), 9.39 (t, J = 5.5 Hz, 1H).
ＨＲＭＳ（ＥＳＩ＋）：Ｃ_１３Ｈ_１０ＣｌＮ_４Ｏ［Ｍ＋１］の計算値：２７３．１５、実
測値２７３．２５。 {4-[(Cyanomethyl) carbamoyl] phenyl} boronic acid (4.2 g, 20.6 m)
mol), 2,4-dichloropyrimidine (4.3 g, 28.8 mmol), potassium carbonate (2.8 kg, 20.6 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II). Complex with dichloromethane (1: 1) (84 mg)
, Of 0.10 mmol), the suspension in acetonitrile (21 mL) and water (11 mL), was sparged with _{N 2} 30 minutes. The mixture was heated to 75 ° C. until the reaction was complete. The mixture was cooled to 60 ° C. and the layers were separated. An aqueous N-acetylcysteine solution (6 mL) was added, followed by water (15 mL). The mixture was cooled to 20 ° C. By filtering the solid _{, washing with H 2} O / CH ₃ CN (3: 1) and drying at 50 ° C., 4- (2-chloropyrimidine-4-yl) -N- (2-chloropyrimidine-4-yl) -N- ( Cyanomethyl) benzamide was obtained:

^{1 1} H NMR (300 MHz, DMSO-d ₆ ): δ 4.36 (d, J = 5.5 Hz, 2H), 8.05 (m,
J = 8.5 Hz, 2H), 8.24 (d, J = 5.3 Hz, 1H), 8.32 (m, J = 8.5 Hz,
2H), 8.89 (d, J = 5.2 Hz, 1H), 9.39 (t, J = 5.5 Hz, 1H).
HRMS (ESI +): _{Calculated value of C 13} H ₁₀ ClN ₄ O [M + 1]: 273.15, measured value 273.25.

¹H NMR (DMSO-d₆): 9.33 (t, J = 5.5 Hz, 1H), 9.24 (s, 1H), 8.48 (d,
J = 5.1 Hz, 1H), 8.24 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.5 H
z, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 5.2 Hz, 1H), 6.58
(d, J = 8.9 Hz, 2H), 5.20 (t, J = 5.8 Hz, 1H), 4.66 (t, J = 5
.4 Hz, 1H), 4.35 (d, J = 5.4 Hz, 2H), 3.57 (q, J = 5.8 Hz, 2H),
3.08 (q, J = 5.8 Hz, 2H)；ＨＲＭＳ（ＥＳＩ＋）：Ｃ_２１Ｈ_２１Ｎ_６Ｏ_２［Ｍ
＋１］の計算値：３８９．１７、実測値：３８９．２７。 In a flask, 4- (2-chloropyrimidine-4-yl) -N- (cyanomethyl) benzamide (6.7 g, 24.6 mmol), 2-((4-aminophenyl) amino) ethanol (7.5 g, 49). .3 mmol, 2.0 eq), i-Pr ₂ Net (4.8 g, 36)
.. 9 mmol, 1.5 eq), and DMSO (20 mL) were charged. The resulting solution was stirred at 100 ° C. When the reaction was complete, the solution was cooled to 20 ° C. and then added to 135 mL of water. The resulting slurry was filtered and rinsed with 70 mL of water. Solid i-PrOH
It was reslurried in (70 mL). The resulting slurry was filtered and rinsed with i-PrOH. The solid was dried under vacuum, dissolved in 30 mL of THF and heated to 50 ° C. Water (85
mL) was slowly filled and the slurry was cooled to 20 ° C. The resulting solid is isolated by filtration and
Rinse with THF / water (1: 3) and water, dry at 40 ° C. and have the following structure: N-
(Cyanomethyl) -4- (2-((4-((2-Hydroxyethyl) amino) phenyl)
Amino) pyrimidine-4-yl) benzamide (Compound 8) was obtained:

^{1 1} H NMR (DMSO-d ₆ ): 9.33 (t, J = 5.5 Hz, 1H), 9.24 (s, 1H), 8.48 (d,
J = 5.1 Hz, 1H), 8.24 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.5 H)
z, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 5.2 Hz, 1H), 6.58
(d, J = 8.9 Hz, 2H), 5.20 (t, J = 5.8 Hz, 1H), 4.66 (t, J = 5)
.4 Hz, 1H), 4.35 (d, J = 5.4 Hz, 2H), 3.57 (q, J = 5.8 Hz, 2H),
3.08 (q, J = 5.8 Hz, 2H); HRMS (ESI +): C ₂₁ H ₂₁ N ₆ O ₂ [M
+1] calculated value: 389.17, measured value: 389.27.

¹H NMR (400 MHz, DMSO-d₆): δ = 9.33 (t, J = 5.6 Hz, 1H), 9.21 (s
, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.01
(d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 5
.1 Hz, 1H), 6.56 (d, J = 8.4 Hz, 2H), 4.78 (bs, 2H), 4.36 (d, J
= 6.4 Hz, 2H)；ＨＲＭＳ（ＥＳＩ＋）：Ｃ_１９Ｈ_１７Ｎ_６Ｏの計算値［Ｍ＋Ｈ］：３
４５．１５、実測値３４５．２８。 In a flask, 4- (2-chloropyrimidine-4-yl) -N- (cyanomethyl) benzamide (4.0 g, 14.7 mmol), phenylenediamine (3.2 g, 29.3 mm).
ol, 2.0 equivalents), i-Pr ₂ NEt (2.9 g, 22.1 mmol, 1.5 equivalents),
And DMSO (12 mL) were charged. The resulting solution was stirred at 60 ° C. When the reaction was complete, the mixture was cooled to 20 ° C. and then added to 50 mL of water. The resulting slurry was filtered, rinsed with water, followed by rinsing with i-PrOH. Solid to i-PrOH (50)
Reslurried in mL), filtered, rinsed with i-PrOH, dried at 40 ° C. and 4-(2-((4-aminophenyl) amino) pyrimidin-4-yl)-with the following structure:
N- (cyanomethyl) benzamide (Compound 10) was obtained:

^{1 1} H NMR (400 MHz, DMSO-d ₆ ): δ = 9.33 (t, J = 5.6 Hz, 1H), 9.21 (s)
, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.01
(d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 5)
.1 Hz, 1H), 6.56 (d, J = 8.4 Hz, 2H), 4.78 (bs, 2H), 4.36 (d, J
= 6.4 Hz, 2H); HRMS (ESI +): C ₁₉ H ₁₇ N ₆ O calculated value [M + H]: 3
45.15, measured value 345.28.

¹H NMR (DMSO-d₆): 9.82 (s, 1H), 9.64 (s, 1H), 9.33 (t, J = 5.5 Hz,
1H), 8.57 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 8.1 Hz, 2H), (8.04,
J = 8.5 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 H
z, 2H), 7.45 (d, J = 5.0 Hz, 1H), 4.36 (d, J = 5.3 Hz, 2H), 2.03
(s, 3H)；ＨＲＭＳ（ＥＳＩ＋）：Ｃ_２１Ｈ_１９Ｎ_６Ｏ_２［Ｍ＋１］の計算値：３８７
．１６、実測値：３８７．２８。 In a flask, 4- (2-chloropyrimidine-4-yl) -N- (cyanomethyl) benzamide (4.0 g, 14.7 mmol), 4'-aminoacetanilide (2.6 g, 17).
.. 6 mmol, 1.2 eq), i-Pr ₂ Net (2.9 g, 22.1 mmol, 1.5)
Equivalent), and DMSO (12 mL) were charged. The resulting solution was stirred at 120 ° C.
When the reaction was complete, the mixture was cooled to 20 ° C. and MeOH (30 mL) was added slowly. The resulting slurry was filtered and rinsed with MeOH. The solid is reslurried in 40 mL of MeOH, filtered, rinsed with MeOH and dried at 40 ° C. with the following structure 4
-(2-((4-Acetamidephenyl) amino) pyrimidin-4-yl) -N- (cyanomethyl) benzamide (Compound 12) was obtained:

^{1 1} H NMR (DMSO-d ₆ ): 9.82 (s, 1H), 9.64 (s, 1H), 9.33 (t, J = 5.5 Hz,
1H), 8.57 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 8.1 Hz, 2H), (8.04,
J = 8.5 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 H)
z, 2H), 7.45 (d, J = 5.0 Hz, 1H), 4.36 (d, J = 5.3 Hz, 2H), 2.03
(s, 3H); HRMS (ESI +): C ₂₁ H ₁₉ N ₆ O ₂ [M + 1] calculated value: 387
.. 16, measured value: 387.28.

¹H NMR (300 MHz, DMSO-d₆): δ 9.83 (s, 1H), 9.34 (t, J = 5.5 Hz,
1H), 8.62 (d, J = 5.2 Hz, 1H), 8.30 (m, J = 8.6 Hz, 2H), 8.04 (m
, J = 8.6 Hz, 2H), 7.85 (m, J = 8.9 Hz, 2H), 7.51 (d, J = 5.2
Hz, 1H), 7.33 (m, J = 8.9 Hz, 2H), 4.36 (d, J = 5.4 Hz, 2H), 4.2
0 (s, 2H), 3.98 (dd, J = 5.9, 4.19 Hz, 2H), 3.62 - 3.79 (m, 2H).
ＨＲＭＳ（ＥＳＩ＋）：Ｃ_２３Ｈ_２１Ｎ_６Ｏ_３［Ｍ＋１］の計算値：４２９．１７、実
測値：４２９．０。 4- (2-Chloropyrimidine-4-yl) -N- (cyanomethyl) benzamide (2.
0 g, 7.2 mmol), 4- (4-aminophenyl) morpholine-3-one (1.4 g)
, 7.2 mmol) and zinc dichloride (98 mg, a mixture of N- methylpyrrolidinone in Non (10 mL) of 0.72 mmol), and sparged with _{N 2} 10 minutes, then to 90 ° C. until the reaction is deemed complete Heated. The mixture was cooled to 50 ° C. and then water (15 mL) was added slowly to the reaction mixture. The resulting slurry was cooled to 20 ° C., the solid was filtered, rinsed with water and dried. The solid was dissolved in 15 mL DMSO and heated to 50 ° C. Methanol (25 mL) was added to the mixture and then cooled to 20 ° C. The resulting solid is filtered, rinsed with MeOH, dried under vacuum at 60 ° C. and N- (cyanomethyl) -4- (2-{[4- (3-oxomorpholine-4-yl) yl) having the following structure: ) Phenyl] amino} pyrimidin-4-yl) benzamide (Compound 13) was obtained:

^{1 1} H NMR (300 MHz, DMSO-d ₆ ): δ 9.83 (s, 1H), 9.34 (t, J = 5.5 Hz,
1H), 8.62 (d, J = 5.2 Hz, 1H), 8.30 (m, J = 8.6 Hz, 2H), 8.04 (m)
, J = 8.6 Hz, 2H), 7.85 (m, J = 8.9 Hz, 2H), 7.51 (d, J = 5.2
Hz, 1H), 7.33 (m, J = 8.9 Hz, 2H), 4.36 (d, J = 5.4 Hz, 2H), 4.2
0 (s, 2H), 3.98 (dd, J = 5.9, 4.19 Hz, 2H), 3.62 --3.79 (m, 2H).
HRMS (ESI +): C ₂₃ H ₂₁ N ₆ O ₃ [M + 1] calculated value: 429.17, measured value: 429.0.

(Example 7)
This study studied CYT-0 for hepcidin production in HepG2 cells, hepatocellular carcinoma cell lines.
The effect of 387 was characterized. Bone morphogenetic protein (BMP) is a constitutively active I
It has been shown to be involved in the transcriptional induction of hepcidin in hepatocytes by promoting the linkage between type I BMP receptor kinase (BMPR-kinase) and type I BMPR-kinase (Andriopoulos et al., Nat. Genet, 2009, Vol. 41 (No. 4): pp. 482-7; Zhao
Et al., J Clin Invest, 2013, Vol. 123 (No. 6): pp. 2337-43). this is,
The result is phosphorylation and activation of type I BMPR-kinase, followed by downstream activation of the effector SMAD protein (SMAD 1/5/8), followed by nuclear transfer in collaboration with SMAD4 (Wrana, Cold Spring). Harb Perspect Biol,
2013, 5: a011197).

HepG2 cells were pre-incubated with CYT-0387 (range 0 μM-10 μM) for 2 hours in the presence of 1% FBS and then stimulated with 10 ng / mL BMP6 for 6 hours. Total RNA was isolated from cells and analyzed for hepcidin levels by qRT-PCR. Using GUSB (glucuronidase, beta) as a housekeeping control,
The levels measured by qRT-PCR were normalized. Calculate the percentage of hepcidin multiple change induction (100% equal to hepcidin induction in vehicle-treated cells), Table 9
Summarized in. The results showed that CYT-0387 resulted in dose-dependent inhibition of BMP6-mediated hepcidin induction.

HepG2 cells were gradually increased in concentration in the presence of 1% FBS CYT-0387 (0.
Pre-incubated with 02-10 μM CYT387) for 2 hours, then 10 ng
Stimulated with / mL BMP6 for 30 minutes. Protein is extracted from the lysed cells and phospho-
Immunoblot analysis was used with antibodies specific for SMAD1 (Ser463 / 465), phospho-SMAD5 (Ser463 / 465) and phospho-SMAD8 (Ser465 / 467) and β-actin. Densitometry software (
Image Studio) was used to quantify raw phospho-SMAD 1/5/8 levels and normalize to β-actin levels. Percentages of phospho-SMAD 1/5/8 levels were calculated (100% equal to phospho-SMAD 1/5/8 levels of vehicle-treated cells stimulated with 10 ng / mL BMP6) and summarized in Table 9. The result is C
It was shown that YT-0387 results in dose-dependent inhibition of BMP6-mediated phospho-SMAD 1/5/8 levels.

^a n=2の平均誘導。
^b SD:標準偏差。
^c n=6の平均誘導。

^{Mean induction of a} n = 2.
^b SD: Standard deviation.
^{mean induction of c} n = 6.

In addition, biochemical binding assays (DiscoveRx) and in vitro enzyme inhibition assays (LanthaScreen, Life Technologies) were performed to perform CYT-0387 type I BMPR-kinases (ALK2, ALK3, and ALK6).
) Was determined for binding affinity and inhibitory activity. Transforming growth factor beta receptor 1 (TGFBR1, ALK5) was used as a control to determine selectivity for type I BMPR-kinase. The results are summarized in Table 10 and CYT-0387 is ALK.
It was shown to have higher affinity and inhibitory activity for ALK2 and ALK6 as compared to 3.

^a AVG:n=3の平均値。
^b SD:標準偏差。

^a AVG: The average value of n = 3.
^b SD: Standard deviation.

(Example 8)
A study will be conducted to investigate the effect of CYT-0387 preparation on the treatment of metastatic non-small cell lung cancer (NSCLC) or metastatic pancreatic ductal adenocarcinoma (PDA). In one study, patients with metastatic Carstenrat sarcoma oncogene homologue (KRAS) mutated NSCLC who failed platinum-based chemotherapy were treated with CYT-0387 for at least one 28-day treatment cycle. Formulation alone, trametinib alone, or CYT-03
Administer a combination of 87 and trametinib. The CYT-0387 preparation (which may contain CYT-0387 dihydrochloride monohydrate form II in tablet format) is 00 m once or twice daily.
It can be orally administered in doses of g, 150 mg, 200 mg, 250 mg, or 300 mg, and trametinib (N- (3- {3-cyclopropyl-5-[(2-fluoro-4-)]
Iodine phenyl) amino] -6,8-dimethyl-2,4,7-trioxo-3,4,5,6
7-Tetrahydropyrido [4,3-d] pyrimidin-1 (2H) -yl} phenyl) acetamide) can also be referred to by the chemical name) once daily at 0.5 mg, 1 mg, or 2 mg. It can be administered orally at a dose. The study included patients with KRAS-mutated metastatic or recurrent non-small cell lung cancer, and these patients were included in RECIST v.
1.1, and Eastern Cooperative Oncology Grou
He has measurable lesions as 0 or 1 of p (ECOG) Performance Status and has received previous treatment with platinum-based chemotherapy or previous chemotherapy up to two lines.

In another study, patients with epidermal growth factor receptor (EGFR) mutated, EGFR tyrosine kinase inhibitor (TKI) untreated metastatic NSCLC were treated with erlotinib alone for at least one 28-day treatment cycle. Or administer a combination of CYT-0387 and erlotinib. The CYT-0387 preparation (which may contain CYT-0387 dihydrochloride monohydrate form II in tablet format) is once or twice daily, 100 mg, 150 mg, 20
It can be administered orally in doses of 0 mg, 250 mg, or 300 mg, and is referred to by the chemical name erlotinib (N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) 4-quinazoline amine). Can also be used), 25 mg, 100 once a day
It can be orally administered at a dose of mg or 150 mg. For this study, Easte
rn Cooperative Oncology Group (ECOG) Perfo
EGFR exon 19 deletion or exon 21 (L858R) with ramance Status 0, 1, or 2, who have never received previous treatment or platinum-based chemotherapy
) Patients with metastatic NSCLC with substitution mutations are added.

In an additional study, capecitabine and CYT-0387 (CYT-03) were used in patients with recurrent or refractory metastatic pancreatic adenocarcinoma during at least one treatment cycle of 21 days.
87 Dihydrochloride monohydrate having Form II in tablet format) or a combination of oxaliplatin, capecitabine, and CYT-0387 is administered. CYT-038
7 formulations (which may include CYT-0387 dihydrochloride monohydrate form II in tablet format) once or twice daily, 100 mg, 150 mg, 200 mg, 250 mg, or 30
It can be orally administered at a dose of 0 mg. Capecitabine (Pentyl [1- (3,4-dihydroxy-5-methyltetra-2-yl) -5-fluoro-2-oxo-
(Also referred to by the chemical name of 1H-pyrimidine-4-yl] carbamate) can be orally administered twice daily for 14 days, followed by a 7-day break, until the end of the procedure. Oxaliplatin ([(1R, 2R) -cyclohexane-1,2-diamine] (also referred to by the chemical name of ethanedioato-O, O') platinum (II)) is used for each of the 21-day treatment cycles. It can be administered intravenously over 120 minutes on the first day.
Patients have relapsed or refractory metastatic pancreatic adenocarcinoma, RECIST v1.1 and Eastern Cooperative Oncology Group (ECOG)
He has 0 or 1 measurable lesions according to Performance Status and has been previously treated with a gemcitabine-containing regimen.

The study was conducted at various treatment points in the Response Analysis Cri.
Safety, toxicity, resistance, complete response (C) as assessed by teria In Solid Tumor (Guidelines for determining the therapeutic effect of solid tumors) (RECIST) v1.1.
R) or partial response (PR) or unchanged (SD), overall survival (ie, between treatment and death for any cause), progression-free survival (ie, RECIST criteria v1.1 from the first dosing date of the study) Until the first evidence of death or clear disease progression based on
, And / or some factors including, but not limited to, the overall response rate (ie, the percentage of patients achieving a complete or partial response).

Each of the references, including all patents, patent applications and publications cited in this application, is incorporated herein by reference in its entirety as if each of them were individually incorporated. .. Further, in the above teachings of the invention, those skilled in the art may make certain modifications or variations to the invention, and these equivalents are still defined in the claims of the present application. It will be appreciated that it is within the scope of the present invention. Each of the references, including all patents, patent applications and publications cited in this application, is incorporated herein by reference in its entirety as if each of them were individually incorporated. .. Further, in the above teachings of the invention, those skilled in the art may make certain modifications or variations to the invention, and these equivalents are still defined in the claims of the present application. It will be appreciated that it is within the scope of the present invention.

In a preferred embodiment of the invention, for example, the following are provided.
(Item 1)
N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) Benzamide dihydrochloride monohydrate form II;
N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-
Il) Benzamide monohydrochloride anhydrous form I; and N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-
Il) Benzamide monohydrochloride anhydrous form III
A compound selected from the group consisting of.
(Item 2)
Item 2. The compound according to Item 1, which is in crystalline form.
(Item 3)
Items 1 and 2 above, wherein the crystal form is N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate form II. Crystal form.
(Item 4)
Crystals at T = 100 ° K, a = 10.2837 (6) Å, b = 10.4941
(6) Å, c = 11.5143 (7) Å, α = 83.297 (2) °, β = 87.649
(2) The crystal morphology according to Item 3 above, which has a unit lattice parameter of °, γ = 67.445 (2) °, and a triclinic P-1 space group.
(Item 5)
Item 3. The crystal morphology according to Item 3, characterized by the powder X-ray diffraction (XRPD) pattern substantially shown in FIG.
(Item 6)
Approximately 7.7 °, 19.3 °, 24.0 °, 25.7 °, and 29.6 ° 2-θ ± 0.2
Item 3. The crystal morphology according to Item 3, characterized by a powder X-ray diffraction (XRPD) pattern having a peak at ° 2-θ.
(Item 7)
Item 3. The crystal morphology according to Item 3, characterized by the differential scanning calorimetry (DSC) pattern substantially shown in FIG.
(Item 8)
Item 3. The crystalline morphology according to item 3, characterized by the dynamic vapor adsorption (DVS) pattern substantially shown in FIG.
(Item 9)
Item 2. The crystal form according to Item 2, wherein the crystal form is crystalline N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride anhydrous form I. ..
(Item 10)
Item 9. The crystal morphology according to item 9, characterized by the powder X-ray diffraction (XRPD) pattern substantially shown in FIG.
(Item 11)
Approximately 13.5 °, 20.9 °, 26.1 °, 26.6 °, and 28.3 ° 2-θ ± 0.
Item 9. The crystal morphology according to Item 9, characterized by a powder X-ray diffraction (“XRPD”) pattern having a peak at 2 ° 2-θ.
(Item 12)
9. The crystal morphology according to item 9, characterized by the differential scanning calorimetry (DSC) pattern substantially shown in FIG.
(Item 13)
Item 2. The crystal form according to Item 2, wherein the crystal form is crystalline N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride anhydrous form III. ..
(Item 14)
Item 2. The crystal morphology according to Item 13, characterized by the powder X-ray diffraction (XRPD) pattern substantially shown in FIG. 7.
(Item 15)
Approximately 12.7 °, 14.6 °, 17.8 °, 19.7 °, and 23.3 ° 2-θ ± 0.
Item 13. The crystal morphology according to Item 13, characterized by a powder X-ray diffraction (“PXRD”) pattern having a peak at 2 ° 2-θ.
(Item 16)
Item 13. The crystal morphology according to Item 13, characterized by the differential scanning calorimetry (DSC) pattern substantially shown in FIG.
(Item 17)
A pharmaceutical composition containing the compound according to any one of the above items 1 to 16.
(Item 18)
Item 17 above, wherein the compound according to Item 1 is N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate form II. The pharmaceutical composition described.
(Item 19)
N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidine-4
-Il) Benzamide dihydrochloride monohydrate Form II, 50 mg, 100 mg, 150 mg
, Or 200 mg of the free base N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide, which is present in an amount corresponding to that of item 17 above.
18 according to the pharmaceutical composition.
(Item 20)
The pharmaceutical composition according to any one of the above items 17 to 19, which is in the form of a tablet.
(Item 21)
After a single oral dose
_{C max} , in the range of 260-405 ng / mL N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide,
_{AUC inf} in the range of 2,057 to 3,214 ng · hr / mL N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide,
_{Alternatively, C max in} the range of 260-405 ng / mL N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide and 2,057-3.
Any of items 17-20 above, which provides both _{AUC inf} in the range of 214 ng · hr / mL N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide. The pharmaceutical composition according to.
(Item 22)
After a single oral administration, an amount equivalent to 300 mg of the free base N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide is N- (cyanomethyl) -4- (2). The pharmaceutical composition according to Item 21 above, which provides a pharmacokinetic profile substantially similar to a dosage form comprising − (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride anhydrous form I.
(Item 23)
A method for the treatment of a disease related to Janus kinase (JAK), which comprises administering to a subject in need an effective amount of the pharmaceutical composition according to item 18 above, wherein the disease is myeloproliferative. Sexual disorders are polycythemia vera (PV), myelofibrosis, thrombocythemia, essential thrombocythemia (
ET), idiopathic myelofibrosis, chronic myelogenous leukemia, systemic mastocytosis (SM), chronic neutrophil leukemia (CNL), myelodysplastic syndrome (MDS) and systemic mastocytosis (SMCD)
) Is a myeloproliferative disorder selected from the group consisting of the methods of item 31 above.

Claims (14)

A combined preparation for simultaneous, separate or continuous use in treatment.
(A) At T = 100K, a = 10.2837 (6) Å, b = 10.4981 (6) Å, c = 11.5143 (7) Å, α = 83.297 (2) °, β = Crystals with unit cell parameters of 87.649 (2) °, γ = 67.445 (2) °, and triclinic P-1 space group;
(B) Figure 5 below:

Powder X-ray Diffraction (XRPD) pattern shown in;
(C) Powder X-ray diffraction (XRPD) pattern with peaks at 7.7 °, 19.3 °, 24.0 °, 25.7 °, and 29.6 ° 2θ ± 0.2 ° 2θ
The activity of compounds and bromodomain-containing proteins characterized by N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate form II. A combined preparation containing a therapeutic agent that inhibits or modulates. At T = 100K, the crystals have a = 10.2837 (6) Å, b = 10.4981 (6) Å, c = 11.5143 (7) Å, α = 83.297 (2) °, β. The combined preparation for use according to claim 1, having a unit cell parameter of = 87.649 (2) °, γ = 67.445 (2) °, and a triclinic P-1 space group. Figure 5:

The combined preparation for use according to claim 1, characterized by the powder X-ray diffraction (XRPD) pattern shown in. Claimed, characterized by a powder X-ray diffraction (XRPD) pattern with peaks at 7.7 °, 19.3 °, 24.0 °, 25.7 °, and 29.6 ° 2θ ± 0.2 ° 2θ. A combined preparation for use according to item 1. Figure 8:

The combined preparation for use according to claim 1, characterized by the differential scanning calorimetry (DSC) pattern shown in. Figure 14:

The combined preparation for use according to claim 1, characterized by the dynamic vapor adsorption (DVS) pattern shown in. The combined preparation for use according to any one of claims 1-6, wherein the therapeutic agent is a bromodomain-containing protein (BRD) inhibitor. The combined preparation for use according to any one of claims 1-6, wherein the therapeutic agent is a BRD4 inhibitor. The combined preparation for use according to any one of claims 1 to 8, wherein the compound is provided in a pharmaceutical composition in solid form. Claim that the compound is present in an amount corresponding to 50 mg, 100 mg, 150 mg, or 200 mg of the free base N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide. 9 Combined preparations for use. The combined preparation for use according to claim 9 or 10, wherein the compound is in the form of a tablet. A combined preparation for use according to any one of claims 9-11, wherein, after a single oral administration, the composition is:
C in the range of 260-405 ng / mL N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide _max ,
AUC in the range of 2,057 to 3,214 ng · hr / mL N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide _inf ,or
C in the range of 260-405 ng / mL N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide _max And AUC in the range of 2,057 to 3,214 ng · hr / mL N- (cyanomethyl) -4- (2- (4-morpholinophenylamino) pyrimidin-4-yl) benzamide. _inf Both
To provide, combined preparations. A combined preparation for use according to any one of claims 1-12, for use in methods for the treatment of diseases associated with Janus kinase (JAK), wherein said. Diseases include true erythropoiesis (PV), myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis, chronic myelogenous leukemia, systemic obesity cytology (SM), chronic favor A combined preparation that is a myeloproliferative disorder selected from the group consisting of neutrogenic leukemia (CNL), myelodysplastic syndrome (MDS) and systemic obesity cell disease (SMCD). A combined preparation for use according to any one of claims 1 to 13, for use in methods for the treatment of primary myelofibrosis.

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